IMPACT

Development and Implementation of a Peer-Navigation Intervention to Improve Research Literacy in Pediatric Cancer Trials

Type of Cancer: Pediatric Cancer

Awardees:

• Paula Aristizabal, MD (Rady Children’s Hospital; UC San Diego Health)
• Elena Martinez, PhD (Moores Cancer Center at UC San Diego Health)

Whereas Hispanic children will comprise 33% of the U.S. population by 2060 and have higher incidence of certain cancers, their participation in biomedical research is critically low and they have poorer survival rates than non-Hispanic Whites. Interventions to improve research literacy (capacity to understand and act on information to make decisions about research) and clinical trial participation, particularly for Hispanics, are lacking. The objective of this proposal is to improve research literacy in parents of children with cancer and increase clinical trial participation, particularly for Hispanics by developing and implementing a culturally and linguistically tailored peer-navigation intervention. By increasing minority participation in clinical trials, we can effectively translate discoveries and treatments equally, and, ultimately, improve equity of survival among diverse populations.

A Novel Role for Histidine Kinase Activity in Neuroblastoma Pathogenesis

Type of Cancer: Pediatric Cancer

Awardees:

• Peter Zage, MD, PhD (Rady Children’s Hospital; UC San Diego Health)
• Tony Hunter, PhD (Salk Institute for Biological Studies)

Children with aggressive neuroblastoma have poor cure rates despite intensive treatment, and new treatments are needed. Treatments that inhibit important proteins and pathways in neuroblastoma are likely to be more effective with fewer side effects. In our initial experiments, we have identified an association between expression of the NME1 gene and the survival rates of children with neuroblastoma. NME1 can act as a histidine kinase, by adding phosphate to the amino acid histidine in other proteins in neuroblastoma cells, representing a previously undiscovered way for cells to control the function of proteins required for neuroblastoma growth and survival. We propose to evaluate the associations of NME1 expression in tumor samples from children with neuroblastoma with their survival rates and other tumor features, and we will explore how NME1 functions to affect neuroblastoma growth, survival, and spread. The results of these studies will likely identify new proteins that could serve as targets for new types of treatment, leading to improved success of neuroblastoma therapy and improved chances of survival for children with neuroblastoma.

Research Focus: Tissue-specific role of SMARCB1 in pediatric rhabdoid tumors

Type of Cancer: Pediatric Cancer

Awardees:

• Frank B. Furnari, PhD (UCSD Ludwig Institute for Cancer Research)
• John Crawford, MD (Rady Children’s Hospital)

This project aims to identify the mechanisms underlying initiation of pediatric rhabdoid tumors of the kidney and atypical teratoid rhabdoid tumors (ATRT) of the brain, which result from deletion of the SMARCB1 gene. To determine why SMARCB1 deletion initiates tumors only in certain tissues and developmental stages the project will investigate differences in the effect of eliminating SMARCB1 expression on cells of different tissue types and attempt to identify potential therapeutic targets which could aid in the treatment of patients with these lethal childhood tumors, which currently have very limited therapeutic options.

Research Focus: Discovery of non-coding oncogenic mutations in pediatric acute lymphoblastic leukemia using ATAC-seq and Hi-C

Type of Cancer: Pediatric Cancer

Awardees:

• Graham McVicker, PhD (Salk Institute for Biological Studies)
• Jesse Dixon, PhD (Salk Institute for Biological Studies)
• Dennis Kuo, MD (Rady Children’s Hospital)

Acute Lymphoblastic Leukemia (ALL) is the most common form of cancer in children. Studies of ALL tumors have led to improved therapies, and increased long-term survival rates in children from ~58% in the 1970s to over 90% today. Yet 10-20% of ALL patients relapse following their initial treatment, and these patients have a grim prognosis with survival rates between 21% and 53%. Therefore, there is a need for improved therapies stemming from a better understanding of the molecular events that promote ALL progression and relapse. We hypothesize that some genetic mutations that are important for ALL onset and relapse have remained undiscovered because they are located in parts of the genome that are difficult to study. Specifically, most studies have focused on mutations that directly affect protein-coding genes, rather than “non- coding regulatory” mutations that affect which genes are expressed. We propose to develop new approaches to identify non-coding mutations in ALL tumors. The basis for our approach is computational analysis of data from new methods (known as ATAC-seq and Hi-C) that provide information about the location and 3D organization of non-coding regulatory sequences in the genome. We will perform ATAC-seq and Hi-C experiments on 20 ALL tumor samples from patients at Rady Children’s Hospital-San Diego and use the resulting data to identify non-coding regulatory mutations. Any non-coding regulatory mutations that we discover will help illuminate the molecular causes of ALL onset and relapse, and could eventually lead to improvements in targeted therapy.

Research Focus: Identification of therapeutic targets of B-ALL using Boolean logic

Type of Cancer: Pediatric Cancer

Awardees:

• Dabashis Sahoo, PhD (Moores Cancer Center at UC San Diego Health)
• Deborah Schiff, MD (Rady Children’s Hospital)

B-cell acute lymphoblastic leukemia (B-ALL) is the most common childhood cancer. Almost all children can be cured of this disease using standard treatment options. Reducing toxicity, rate of infections, and behavioral changes are the main goals in developing next-generation targeted therapies. B-ALL cells possess the ability to go through a series of intermediate steps towards a less aggressive state. The early steps along this path contain the most aggressive cell types that can be targeted to cure the disease. Molecular or epigenetic drivers that characterize the most aggressive state is poorly understood. We have developed mathematical tools to understand logical rules of gene expression patterns of these aggressive cell types. This will help us to develop targeted therapies for B-ALL.

Research Focus: Deciphering the Role of RNA Editing in Leukemia Stem Cell Generation and Pediatric Acute Leukemia Relapse

Type of Cancer: Pediatric Cancer

Awardees:

• Preethi Ganesan, MD, PhD (Rady Children’s Hospital)
• Catriona Jamieson, MD, PhD (Moores Cancer Center at UC San Diego Health)

Acute lymphoblastic leukemia (ALL) is the commonest childhood cancer and leukemia relapse after treatment is an important cause of cancer-related death. Leukemia relapse is caused by a distinct subset of cells called “leukemia stem cells” (LSC) that have the unique capacity to maintain themselves for a long period of time while remaining in a dormant state. This enables them to evade elimination by conventional cancer treatments such as chemotherapy and radiotherapy, which preferentially kill rapidly multiplying cells. This project aims to study the signals and pathways that are important in propagating these LSC. Previous work in our lab in chronic myeloid leukemia (CML) has shown that inflammatory signals activate a family of enzymes called adenosine deaminase acting on RNA (ADAR) which generates LSC and leads to progression of CML from an indolent “chronic phase” to an aggressive “blast crisis” phase that is resistant to treatment. However, the role of ADAR in generating LSC in ALL is not known. Work in our lab showed that there is high expression of ADAR1 in human ALL. Hence we have established a mouse model of ALL by transferring cells purified from leukemia patient’s bone marrow into immune-deficient mice. We will perform latest molecular tests that will allow us to track the functional activity of ADAR1 in LSC in live mice that harbor human ALL. This will enable us to understand how ADAR mediates LSC maintenance and dormancy, thereby revealing novel targets that may be utilized in elimination of the LSC that drives leukemia relapse.

Research Focus: Developing targeted therapy for Ewing sarcoma metastasis

Type of Cancer: Pediatric Cancer

Awardees:

• Jing Yang, PhD (Moores Cancer Center at UC San Diego Health)
• Sun Choo, MD (Rady Children’s Hospital)

Ewing’s sarcoma is a malignant tumor that commonly appears in a bone. It usually occurs between 10-20 years of age. About 25% of patients present with clinically detectable metastatic disease. Because of the possibility of undiagnosed metastatic disease, chemotherapy, surgery and radiation therapy are applied for all patients. Despite aggressive therapy, almost no improvement has been seen in patients with metastatic disease (80% mortality). The failure to stop Ewing’s sarcoma metastasis is due to the lack of understanding about the molecular pathways that regulate its spreading. To address this unmet need, we hypothesize that a group of genes that regulate the generation and function of a specialized group of embryonic stem cells (neural crest cells) are reactivated to allow Ewing’s sarcoma cells to metastasize. Our previous study show that expression of one such gene (Twist1) is associated with metastasis and poor survival in Ewing’s sarcoma patients. Therefore, we propose to examine Twist1 and other genes regulated by Twist1 in Ewing sarcoma metastasis and to test whether drugs targeting these genes will block metastasis with higher specificity and fewer side effects than conventional therapy.

In the short term, the proposed research provides new prognostic markers to identify high-risk Ewing sarcoma patients for personalized treatment options. In the long term, the proposed research could lead to novel therapeutic regimens that reduce morbidity from ineffective conventional therapies and save the lives of countless children affected with metastatic Ewing’s sarcoma.

Research Focus: Novel Kinase Inhibitors in Combination with Retinoic Acid for Neuroblastoma

Type of Cancer: Pediatric Cancer

Awardees:

• Peter Zage, MD, PhD (Rady Children’s Hospital)

Children with aggressive neuroblastoma have poor cure rates despite intensive treatment that includes chemotherapy, surgery, radiation therapy, and maintenance therapy with 13-cis- retinoic acid (CRA). Aggressive neuroblastoma tumors frequently relapse after the completion of treatment, likely due to residual tumor cells that are resistant to the effects of CRA. Kinases are proteins that can stimulate tumor cell growth and survival, and a large number of new drugs are available that block or inhibit kinase function, resulting in tumor cell death. Identification of individual kinases needed for neuroblastoma cell survival after CRA treatment will lead to new treatment combinations for children with relapsed neuroblastoma using these new kinase inhibitors combined with CRA. In our initial experiments, we have identified a kinase named “MEK,” a member of a key signaling pathway in cancer cells, as a kinase needed for neuroblastoma tumor cell survival after CRA treatment. We propose to evaluate the role of MEK in neuroblastoma tumor cell resistance to CRA and the effectiveness of treatment with CRA combined with new drugs that block MEK activity. The results of these studies will identify treatment combinations using readily available drugs that can be rapidly tested in clinical trials, leading to improved success of neuroblastoma therapy and improved chances of survival for children with neuroblastoma.

Research Focus: HPV Vaccination Rates, and Knowledge, Attitude, and Behavior (KAB) among Male and Female Pediatric Cancer Survivors Ages 11-12 Years and their Parents

Type of Cancer: Pediatric Cancer

Awardees:

• Jesse Nodora, DPhil (UC San Diego Health)
• Paula Aristizabal, MD (Rady Children’s Hospital–San Diego)

As of 2011, about 388,500 of U.S. cancer survivors were first diagnosed when they were younger than 21 years of age and many ultimately will be considered cured. Multiple published reports show that pediatric cancer survivors carry a higher risk of developing second malignancies than the general population. There is a scarcity of data on human papillomavirus (HPV) vaccination rates, barriers and facilitators for vaccine uptake, and completion rates among pediatric cancer survivors and no data exist for boys. Without such data, these children will not benefit from the tremendous cancer preventive ability of the HPV vaccine. In partnership with the Rady Children’s Hospital San Diego’s Long-Term Follow-Up ”Thriving After Cancer” Clinic, our study will assess HPV vaccination rates and knowledge, attitude, and behavior among 72 pediatric cancer survivors (36 girls and 36 boys) ages 11-12 years and their parents. Our pilot study is timely and significant as it will inform the development of future research and interventions to improve HPV vaccination uptake and completion in childhood cancer survivors.

Research Focus: The Role of UBE4B in Neuroblastoma Differentiation

Type of Cancer: Pediatric Cancer

Awardees:

• Peter Zage, MD, PhD (Rady Children’s Hospital–San Diego; UC San Diego Health, Pediatrics)

Children with aggressive neuroblastoma have poor cure rates despite intensive treatment. Growth factor receptors (GFRs) are proteins on the surfaces of tumor cells that transmit signals driving the cells to grow, divide, and spread. UBE4B is protein inside tumor cells required for GFR destruction, thereby turning off the signals, and we have shown that the levels of UBE4B are associated with the survival of children with neuroblastoma, suggesting a new connection between proteins that control GFR destruction and the growth of neuroblastoma tumors. Treatment of neuroblastoma tumors often causes tumor cell differentiation (or maturation), and we have previously shown that low UBE4B levels are associated with reduced tumor cell maturation, suggesting that GFR destruction controlled by UBE4B may help neuroblastoma tumors respond to treatment. However, the ways in which UBE4B controls neuroblastoma tumor differentiation are not known. We believe that UBE4B controls the levels and activity of GFRs in neuroblastoma tumor cells and that low levels of UBE4B lead to increased levels of GFRs and to blockage of pathways leading to differentiation. We propose to evaluate the ways in which UBE4B controls neuroblastoma tumor cell differentiation and affects responses to treatment. The results of these studies will provide a better understanding of neuroblastoma differentiation, and the potential effectiveness of treatments combining drugs that cause neuroblastoma differentiation with new drugs also represents an opportunity to develop treatment combinations that can be rapidly tested in clinical trials, leading to better neuroblastoma therapy success rates and improved survival rates for children with neuroblastoma.

Research Focus: Biophysical Markers and Patient Reported Outcomes: Gaining Objectivity in Assessing Acute on Chronic Pain in Children with Serious Illnesses

Type of Cancer: Pediatric Cancer

Awardees:

• Deborah Schiff, MD (Rady Children’s Hospital–San Diego)
• Toluwalase Ajayi, MD (UC San Diego Health, Pediatrics)

At any one time, thousands of children are living with cancer. Children with cancer experience significant suffering throughout the course of illness, whether that illness culminates in cure or not. Pain is the most common and disabling symptom in children with cancer. It can start at the moment of diagnosis and continues during disease progression. The World Health Organization ladder describes an approach to medical therapies for pain management starting with non-opioid therapies for mild pain and progressing to opioid medications for moderate to severe pain. In cases of severe or refractory pain where the use of first-line and opioid therapies is inadequate, ineffective, or creates untoward side effects, the number of viable alternatives for pain management is limited.

Achieving effective and prompt pain control is one of the most challenging goals in pediatric oncology in order to minimize the negative effects of pain on the quality of life of the patients and their families. The proposed study will enroll children who suffer cancer/chemotherapy-related pain in order to better understand how to assess their pain-related distress and thus treat their suffering. If successful, results of our study would lay the groundwork for future investigations that could revolutionize how physicians treat children with cancer-related pain. Further investigations include extending this research to the adult population, studying how physicians meaningfully use the data and then investigating the integration of patient-reported outcomes (PROs) with these concrete objective measures for comprehensive assessment and treatment of pain.

Targeting Fibroblast Heterogeneity to Improve Surgical Outcomes in Pancreatic Cancer

Type of Cancer: Pancreatic Cancer

Awardees:

• Michael Bouvet, MD (Moores Cancer Center at UC San Diego Health)
• Ronald M. Evans, PhD (Salk Institute for Biological Studies)

Currently, the only curative treatment for pancreatic cancer is surgical resection. However, for the majority of patients that undergo surgery, some cancer cells are inadvertently left behind and tumors regrow. The recent development of fluorescence-guided surgery and photoimmunotherapy techniques have tremendous potential to capture these remaining tumor cells and allow surgeons to achieve truly curative resections where patients remain disease free. Importantly, these revolutionary new approaches rely on the delivery of labeled drugs to tumors. One major roadblock for their successful application in pancreatic cancer comes from the presence of a cellular support network (or “stroma”) that surrounds the tumor, forming a physical barrier that hides tumor cells and prevents drugs from reaching them. This stromal response is largely driven by a collection of cells known as cancer associated fibroblasts (CAFs). In breakthrough studies, we have found that therapeutically targeting the Vitamin D Receptor (VDR) in CAFs can destabilize this stromal barrier. Here, we will use mouse models that accurately mimic human disease to test if VDR-targeted therapies can aid fluorescence-guided surgery and photoimmunotherapy to improve surgical success rates. In addition, we will use recent advances in single cell genomic analyses to understand precisely how VDR-targeted therapies impact the different types of CAFs that establish stromal barriers for drug delivery. In summary, by combining VDR-targeted therapies with fluorescence-guided surgery and photoimmunotherapy, we believe we are poised to dramatically enhance the success of surgical resection, paving the way for increased patient survival of this deadly disease.

Understanding and Targeting NRF2 in Pancreatic Cancer

Type of Cancer: Pancreatic Cancer

Awardees:

• Michael Karin, PhD (Moores Cancer Center at UC San Diego Health)
• Andrew Lowy, PhD (Moores Cancer Center at UC San Diego Health)
• Jorge Moscat, PhD (Sanford Burnham Prebys Medical Discovery Institute)

We have identified a protein that is called NRF2, whose expression is elevated in the pancreas of patients suffering from chronic pancreatitis, an inflammatory disease that greatly increases pancreatic cancer risk. Importantly, NRF2 expression remains elevated in established pancreatic cancer. In preclinical studies we found that inhibition of NRF2 expression slows down development of pancreatic cancer in mice subjected to either acute or chronic pancreatitis. These results suggest that developing drugs to lower NRF2 or kill cells with elevated NRF2 may be used to prevent pancreatic cancer in high-risk individuals and may also be effective against established pancreatic cancer. To better understand how NRF2 accelerates the development of pancreatic cancer and provide us with an experimental system suitable for testing of NRF2 targeting drugs, we generated a new mouse model in which the formation of pancreatic cancer is strictly dependent on NRF2. We will use these mice to study how NRF2 controls pancreatic cancer metabolism and determine whether known drugs that inhibit certain aspects of NRF2’s tumorigenic activity can be used to prevent pancreatic cancer. We will also asses the therapeutic potential of a new class of prodrugs whose conversion to fully toxic anticancer drugs is NRF2-dependent. We expect such drugs to selectively kill pancreatic cancer cells that possess high NRF2 activity while sparing normal cells in which NRF2 expression is low. These studies will contribute to development of new procedures for prevention and treatment of pancreatic cancer, the deadliest common human malignancy.

Research Focus: An over-expressed GPCR in pancreatic cancer associated fibroblasts as a novel therapeutic target

Type of Cancer: Pancreatic Cancer

Awardees:

• Paul Insel, MD (Moores Cancer Center at UC San Diego Health)
• Kristiina Vuori, MD, PhD (Sanford Burnham Prebys Medical Discovery Institute)

Pancreatic ductal adenocarcinoma (PDAC) is the most common and deadly form of pancreatic cancer with >93% of PDAC patients dying less than 5 years after their diagnosis. Part of the difficulty in treating PDAC is its characteristic dense scarring (“fibrosis”). This scarring is generated pancreatic cancer associated fibroblasts (PCAFs). This project seeks to build on our recent discovery that PCAFs have high expression of a novel protein on their cell surface. This protein, known as GPCR, is activated by the acidic (low pH) environment that exists in pancreatic cancers. When activated by this low pH, the PCAFs communicate with the PDAC cells to enhance their growth. In this project, UCSD investigators will conduct studies to define additional responses produced by exposure of CAFs to low pH and with Sanford-Burnham- Prebys Cancer Center/Medical Discover Institute (SBP), will assess “libraries” identified and which, as a result, should block the production of scarring and stimulation of PDAC growth by the PCAFs. These studies that combine efforts at UCSD with those at SBP thus focus on the “tumor microenvironment” in which PDAC cells and PCAFs interact and will test the idea that a drug that blocks a special type of GPCR present in PCAF cells can provide a novel way to assist in the treatment PDAC tumors and thus may be a new way to improve the outcome of this very deadly type of cancer.

Research Focus: Irreversible electroporation as an In Situ vaccine for pancreatic cancer

Type of Cancer: Pancreatic Cancer

Awardees:

• Rebekah White, MD (Moores Cancer Center at UC San Diego Health)
• Aaron Miller, MD, PhD (Moores Cancer Center at UC San Diego Health)
• Steven Schoenberger, PhD (La Jolla Institute)

Approximately 40,000 people are diagnosed with pancreatic cancer each year in this country. Unfortunately, most patients—even those with tumors that appear localized on imaging—will eventually develop distant metastatic disease. The goal of immunotherapy is to utilize the patient’s immune system to reject the invading “foreign” tumor like an infection. “In situ vaccination” refers to approaches in which the tumor is made to appear more foreign to generate immune responses against it. Electroporation is a common laboratory technique in which electrical voltage is applied to cells to make holes for intracellular delivery of DNA and RNA. Irreversible electroporation (IRE) is a technique now being used clinically for localized tumors that cannot be removed surgically (locally advanced tumors). Our hypothesis is that IRE stimulates immune responses to tumor cells and that we can augment immune responses to IRE with immunotherapy. We will use mouse models of pancreatic cancer to evaluate the effects of IRE on the immune system. We will evaluate the combination of IRE with immunotherapy drugs that are already available as well as novel agents in development. We envision that this approach will increase the proportion of patients with localized disease who are cured. Since we have already started a clinical IRE program at UCSD, a clinical trial in which an immunotherapy drug is given during or after IRE as adjuvant therapy would likely be feasible within 2-3 years.

Research Focus: Reprogramming Pancreatic Cancer’s Hard Shell

Type of Cancer: Pancreatic Cancer

Awardees:

• Andrew Lowy, MD, (Moores Cancer Center at UC San Diego Health)
• Geoffrey Wahl, PhD (Salk Institute for Biological Studies)

Every day, a San Diegan will be diagnosed with pancreatic cancer, yet only one in 20 will survive for five years after this diagnosis. Pancreatic cancer is the fourth deadliest cancer, yet very little progress has been made in fighting the disease over the last 50 years. Pancreatic cancer is difficult to treat in part because the cancer grows encased in a thick tissue protective layer called the “activated stroma.” Andrew Lowy, MD, (Moores Cancer Center) and Geoffrey Wahl, Ph.D., (Salk) will study a novel way to treat this recalcitrant cancer by focusing on smart-drugs that can reprogram the stroma to allow other smart-drugs to attack the cancer inside.

Research Focus: Therapeutic Reprogramming of Pancreatic Cancer Stroma Via Modulation of p 62 and p 53

Type of Cancer: Pancreatic Cancer

Awardees:

• Andrew Lowy, MD (Moores Cancer Center at UC San Diego Health)
• Geoff Wahl, PhD (Salk Institute for Biological Studies)
• Maria Diaz Meco, PhD (Sanford-Burnham Prebys Medical Discovery Institute)
• Jorge Moscat, PhD (Sanford-Burnham Prebys Medical Discovery Institute)

Pancreatic cancer remains the most deadly common cancer in the U.S. with a five-year survival rate of 6 percent. Despite the fact that fewer persons are diagnosed with pancreatic cancer than many other cancers, this high death rate will likely make it the No. 2 cancer killer by 2020.

Researchers have identified that non-cancerous cells present in pancreatic tumors have lost the function of two critical proteins that normally act to suppress cancer development. This grant will allow new tools to be developed by researchers to rapidly screen through a very large number of drugs in order to identify those which can restore the function of these proteins. By identifying such drugs, they can then be tested as part of a new treatment approach to pancreatic cancer.

“There is a misconception that cancer research projects take years – even decades – to make a lasting impact,” said Garth Powis, DPhil, Director of Sanford- Burnham Cancer Center. “Pedal the Cause is fast-tracking that process. After just one year, research funded by Pedal has led to breakthrough findings significant enough to receive additional funding and sponsorship by the NIH. We are thrilled. It’s Pedal-powered progress.”

Knowledge-Based Planning and Treatment Decision-Making for Gynecologic Brachytherapy

Type of Cancer: Gynecologic Cancer

Awardees:

• Sandra Meyers, PhD (Moores Cancer Center at UC San Diego Health)
• Kevin Moore, PhD (UC San Diego Health)
• Jyoti Mayadev, MD (Moores Cancer Center at UC San Diego Health)

Brachytherapy is a treatment in which radiation is delivered internally, using a device known as an applicator and/or needles to guide a radioactive source directly into the tumor. Using imaging, this radiation dose can be customized to an individual patient’s anatomy, maximizing dose to the tumor while minimizing dose to healthy organs.
Although brachytherapy is an essential component of cervical cancer treatment, centers worldwide are offering less and less brachytherapy. This could be because the treatment process is complex, time consuming, and requires a very skilled team. Doctors use their experience to decide what applicator and needles to use, and physicians with deep brachytherapy experience are a scarce resource. Machine learning is an exciting new technique where large amounts of data are input into advanced computer models to automatically make predictions. In this study, we will use data from hundreds of prior patients’ treatments to make predictions for an individual patient. The machine learning model will be able to look at images of a patient before brachytherapy, and then predict the best applicator for that patient, as well as the radiation dose he/she will receive. This will help doctors make important decisions about a patient’s brachytherapy treatment before they ever enter the operating room! Without brachytherapy, the chance of survival of a cervical cancer patient is reduced by 12%. The tools developed in this study will improve the quality and efficiency of brachytherapy treatments, so that brachytherapy can be used by more centers worldwide.

Epigenetic Profiling of Endometrial Cancer

Type of Cancer: Endometrial Cancer

Awardees:

• Diana Hargreaves, PhD (Salk Institute for Biological Studies)
• Ramez Eskander, MD (Moores Cancer Center at UC San Diego Health)

Endometrial cancer is the fourth most common cancer in women and the most commonly diagnosed gynecologic cancer, and is rising in both incidence and mortality. While the prognosis for patient with early stage endometrial cancer is quite good, those presenting with advanced stage or recurrent disease have a more guarded prognosis. Treatment often involves surgery to remove the uterus and other affected organs. Radiation and/or chemotherapy are sometimes required to help improve outcomes. Despite advances in surgical management and therapeutics, the 5-year survival for patients with advanced stage or recurrent disease approaches 50% and represents a significant unmet clinical need. In an effort to improve outcomes, researchers are looking to leverage knowledge of genetic events caused by mutations in the DNA sequence that promote or “drive” endometrial cancer. This approach is limited, however, by the effectiveness of targeted therapies for each “driver” event. Indeed, many genetic drivers are non-targetable. Alternatively, we hypothesize that the epigenetic signature of endometrial cancer will reveal many more genes with potential “driver” activity based not on genetic mutation, but modifications at regulatory sequences affecting gene expression. Our approach is to profile 20 endometrial cancer samples from patients treated at the Moores Cancer Center, UC San Diego using next-generation sequencing methods. These data will be used to classify endometrial cancers into subtypes and to identify genes on which each subtype depends. Our goal is to develop a classification system based on epigenetic features that will improve diagnosis and help identify novel treatment strategies for endometrial cancer.

Research Focus: Epigenetic Basis of Platinum Drug-resistance in Ovarian Cancer

Awardees:

• Olivier Harismendy, PhD (Moores Cancer Center at UC San Diego Health)
• Stephen Howell, MD (Moores Cancer Center at UC San Diego Health)
• Joseph Ecker, PhD (Salk Institute for Biological Studies)

The majority of patients treated for ovarian cancer receive platinum-based chemotherapy, but 85 percent of patients who initially responded will eventually relapse with a recurrent tumor that is resistant to treatment. Platinum drug resistance is a serious clinical problem affecting thousands of patients every year. With the modern tools of precision medicine and genomics, scientists now have a chance to better understand how tumor cells adapt to and escape the treatment. PEDAL15 funding will allow scientists to apply an experimental system developed to obtain platinum-sensitive and resistant cells that have an identical DNA sequence. Scientists will evaluate why tumors can rapidly adapt to treatment and become resistant. This research is likely to predict why certain ovarian tumors are more likely to become resistant and how soon. It may also lead to the identification of therapies to prevent or delay the onset of platinum resistance.

CLINICAL TRIAL: An Open-Label, Phase 2 Efficacy Study of Temozolomide (TMZ) in Advanced Succinate Dehydrogenase (SDH)-Mutant/Deficient Gastrointestinal Stromal Tumor (GIST)

Type of Cancer: Gastrointestinal Stromal Tumor

Awardees:

• Jason Sicklick, MD, FACS (Moores Cancer Center at UC San Diego Health)
• Adam Burgoyne, MD, PhD (Moores Cancer Center at UC San Diego Health)

Gastrointestinal stromal tumor (GIST) caused by mutations in succinate dehydrogenase (SDH) genes that control sugar metabolism is a rare form of cancer that affects 150-200 patients annually. Making the situation worse, these tumors are inherited, and mostly affect teenagers and young adults. There no effective therapies for treating this cancer, nor are there available research models for studying drugs. However, our group has grown the first human GIST cells that have defects in these sugar genes in order to study this deadly cancer. We have identified temozolomide, a chemotherapy drug taken in pill form, as effective for killing these cells in the laboratory. Furthermore, we successfully treated a small group of UC San Diego GIST patients with temozolomide after they failed traditional GIST treatments. We now aim to perform a clinical trial to scientifically test the effectiveness of this drug in patients with GIST caused by these sugar metabolism defects. We will also check blood levels of sugar breakdown products to determine if these are useful for following treatment responses. Overall, this represents a novel, homegrown, translation from bench-to-bedside using the FDA-approved drug temozolomide to treat a lethal form of cancer that has no effective treatment. We anticipate these studies will: 1) identify the first successful therapy for these GIST patients; and 2) yield new insights into monitoring their drug treatment responses. These studies have the potential for immediately changing clinical care of GIST patients in the prime of life.

Research Focus: Discovering Gastrointestinal Stromal Tumor Weaknesses

Type of Cancer: Gastrointestinal Cancer

Awardees:

• Jason Sicklick, MD (Moores Cancer Center at UC San Diego Health)
• Robert Weschler-Reya, PhD (Sanford Burnham Prebys Medical Discovery Institute)

Gastrointestinal stromal tumor (GIST) is a cancer that arises from nerve cells that control the movement of muscles in the intestine. Many GISTs have a high level of a protein called KIT, which led to the use of a drug called imatinib that could attack KIT. This became the first targeted, personalized treatment of solid tumors. However, it did not completely cure the disease, because some GISTs don’t have the KIT target or develop a drug-resistant form of KIT. Jason Sicklick, MD, (Moores Cancer Center) and Robert Weschler-Reya, Ph.D., (Sanford-Burnham) will use advanced screening technology to discover new drugs that can target GISTs resistant to current therapies.

CLINICAL TRIAL: A Phase 1b Pilot Clinical Trial of Cirmtuzumab, An Anti-ROR1 Monoclonal Antibody, In Combination with Paclitaxel for the Treatment of Patients With Metastatic, or Locally Advanced, Unresectable Breast Cancer

Type of Cancer: Breast Cancer

Awardees:

• Barbara Parker, MD (Moores Cancer Center at UC San Diego Health)
• Rebecca Shatsky, MD (Moores Cancer Center at UC San Diego Health)

Despite recent advances as of 2018, breast cancer remains the second highest cause of cancer-related death in women. While some women are living longer than ever with breast cancer, both triple negative and aggressive types of estrogen positive breast cancer remain life threatening and ultimately resistant to currently approved breast cancer therapies. One theory why many breast cancers become resistant to treatment is that current cancer therapies are not targeting cancer stem cells. Cancer stem cells (or cells with stem cell characteristics) can remain in the body after treatment completes and allow cancer cells to resist chemotherapy, regenerate tumors and spread as metastases. At UC San Diego Moores Cancer Center, we have developed a highly specific immunotherapy called cirmtuzumab that may address this unmet need by targeting cancer stem cells. Laboratory studies by Dr. Thomas Kipps have shown that this immunotherapy combined with chemotherapy decreases growth of patient-derived breast tumors in animals. Our research suggests this therapy may be beneficial to women with advanced, aggressive breast cancer.
Therefore, we have developed a clinical trial to study cirmtuzumab in combination with paclitaxel, a chemotherapy that is safe, well studied, and known to be effective in breast cancer. The goal of this study is to evaluate safety of the combination, to understand benefit to patients, to investigate how the combination inhibits cancer growth, and to determine how to study this combination in the future.

Impact of Metformin on Clonal Hematopoiesis and Clinical Outcomes in Breast Cancer

Type of Cancer: Breast Cancer

Awardees:

• Rafael Bejar, MD, PhD (Moores Cancer Center at UC San Diego Health)
• Dorothy Sears, PhD (Moores Cancer Center at UC San Diego Health)

Clonal hematopoiesis describes a common pre-cancerous condition where blood stem cells gain one or more mutations in cancer-associated genes that allow them to grow and expand abnormally at the expense of their normal counterparts. Chemotherapy triggers DNA damage and inflammation within the bone marrow microenvironment prompting certain blood stem cells with adverse mutations to expand even further, significantly increasing the risk for developing very aggressive blood cancers for which current treatments are ineffective and survival is measured in months. There is a critical need for improved predictive and preventative measures for secondary blood cancers in patients who are otherwise cured from their primary cancer. Metformin is a widely-used diabetes drug that blocks several inflammatory pathways and could have profound effects on the bone marrow microenvironment to reduce the risk of secondary blood cancers in individuals treated with particularly causative chemotherapeutic agents. We will study how treatment with Metformin affects clonal hematopoiesis and disease outcomes in women who received chemotherapy after surgery for breast cancer. Exploring how inflammation after chemotherapy exposure affects mutant blood stem cells leading to predisposition for secondary blood cancers will impact how we screen and follow clonal hematopoiesis in the foreseeable future and integrate preventative efforts long term for breast cancer and other solid tumors.

Enhanced Breast Cancer Risk Prediction from Imputed Gene Expression

Type of Cancer: Breast Cancer

Awardees:

• Hannah Carter, PhD (Moores Cancer Center at UC San Diego Health)
• Graham McVicker, PhD (Salk Institute for Biological Studies)

Early detection remains the strongest determinant of long-term disease-free survival across cancer types, however there is a tradeoff between screening for early detection and the risk of false diagnosis and overtreatment. One strategy to optimize this tradeoff is to stratify individuals by genetic cancer risk and to screen more aggressively in high-risk populations. Genetic risk scores have shown some promise for identifying individuals at risk, however current models use a very simple combination of risk factors and do not account for the complex nature of the underlying biology. In this proposal we will develop new genetic risk scores that incorporate information about (1) the impact of genetic factors on gene expression and (2) the relationship between gene expression and disease risk. This proof-of-principle study will be implemented in breast cancer, but can easily generalize to a number of cancer types and will provide a framework for future studies of cancer risk biology. The long-term goals of this research are to improve our understanding of the genetic mechanisms that drive cancer risk and to enable accurate identification of high-risk individuals that can benefit from additional screening and prevention.

Research Focus: Targeting cellular mechanotransduction in breast cancer metastasis

Type of Cancer: Breast Cancer

Awardees:

• Jing Yang, PhD (Moores Cancer Center at UC San Diego Health)
• Elena Pasquale, PhD (Sanford Burnham Prebys Medical Discovery Institute)

Breast tumors are frequently detected through physical palpation due to their apparent “hardness” compared to the soft normal mammary tissue. The “hardness” of breast tumors correlates with distant metastasis and poor outcome in breast cancer patients. Recent studies show that breast tumors show a 10-50-fold increase of mechanical force exerted on tumor cells compared to normal breast tissues and that mechanical force generated by increasing hardness of breast tumors promotes breast cancer metastasis. However, it is unknown how mechanical force impacts breast cancer metastasis and whether therapeutic targeting of this regulatory mechanism could halt breast cancer progression and metastasis. Our ongoing studies have identified two druggable candidate proteins that are likely to play essential roles in promoting breast tumor invasion and metastasis in response to high matrix rigidities in the tumor microenvironment. In this proposal, we aim to further characterize these two proteins in this novel metastasis regulatory pathway and determine whether therapeutic targeting these two proteins could inhibit breast cancer invasion of surrounding normal tissue and the formation of metastases. In the short term, the proposed research provides new prognostic markers to identify high-risk breast cancer patients for personalized treatment options. In the long term, the proposed research could lead to novel therapeutic regimens targeting cellular mechanotransduction for high-risk breast cancer patients with dense and stiff breast tumors.

Research Focus: Finding New Hereditary Breast Cancer Markers

Type of Cancer: Breast Cancer

Awardees:

• Lisa Madlensky, PhD (Moores Cancer Center at UC San Diego Health)
• Geoffrey Wahl, PhD (Salk Institute for Biological Studies)

Only 10 percent of breast cancer cases are linked to BRCA. Lisa Madlensky, PhD (Moores Cancer Center) and Geoffrey Wahl, PhD (Salk) are working with a family that is strongly suspected of carrying a hereditary breast cancer gene, even though all members are BRCA-negative. The study aims to find a new susceptibility gene for which families with unexplained hereditary breast cancer can be tested. This information could help determine which family members have the gene and therefore need to be monitored carefully or undertake breast cancer prevention measures, and which family members did not inherit the gene and are considered to be at average risk.

Research Focus: Halting Breast Cancer’s Spread

Type of Cancer: Breast Cancer

Awardees:

• Michael Karin, PhD (Moores Cancer Center at UC San Diego Health)
• Geoffrey Wahl, PhD (Salk Institute for Biological Studies)

The spread of cancer cells from the primary tumor to distant organs, termed metastasis, is the leading cause of cancer-related death. Even the removal of early-diagnosed primary breast cancer cannot guarantee prevention of metastatic recurrence many years later. Michael Karin, Ph.D., (Moores Cancer Center) and Geoffrey Wahl, Ph.D., (Salk) will research ways of halting breast cancer metastasis by inhibiting Ubc13 and p38, enzymes involved in controlling metastatic spread.

Research Focus: Cytotoxic Breast Cancer Treatment Effects on Aging

Type of Cancer: Breast Cancer

Awardees:

• Deborah Kado, MD, MS (Moores Cancer Center at UC San Diego Health)
• Jan Karlseder, PhD (Salk Institute for Biological Studies)

With a growing aging U.S. population and an expected increase in cancer survivorship projected to affect more than 60 percent of those over the age of 65, there is concern that the effects of cancer treatments on physiologic reserve may carry long-term undesirable health consequences. Whether accelerated aging affects patients diagnosed with breast cancer, the most common type of cancer to affect women, is unknown. As a result of this grant, a multi- disciplinary team of scientists, clinicians, geriatricians and cancer physician specialists will conduct an integrated effort to understand what anti-cancer therapies do, not only with respect to healthy cells but also to overall health and function. Our ultimate goal is to better understand whether or not chemotherapy may contribute to accelerated aging in breast cancer patients, and if so, identify and target modifiable factors to decrease the risk of not only developing recurrence but also to maximize long-term healthy function and quality of life in these women as they age.

Targeting CD114 Signaling in Pediatric Medulloblastoma

Type of Cancer: Pediatric Brain Cancer

Awardees:

• Peter Zage, MD, PhD (Rady Children’s Hospital; UC San Diego Health)
• Robert Weschler-Reya, PhD (Sanford Burnham Prebys Medical Discovery Institute)
• Pablo Tamayo, PhD (UC San Diego Health)

Children with high-risk, aggressive forms of medulloblastoma (MB) have poor chances of survival despite intensive chemotherapy and significant supportive care, including Granulocyte-Colony Stimulating Factor (GCSF). New treatments that kill MB cells resistant to chemotherapy are likely to reduce the chances of relapse and improve patient outcomes. We have recently found a small number of MB cells that have the Granulocyte-Colony Stimulating Factor (G-CSF) receptor (also called CD114) on their surface. We have shown that these CD114-positive cells grow faster after G-CSF treatment and are more resistant to chemotherapy compared to CD114-negative cells. These CD114-positive cells may contribute to the poor outcomes in children with high-risk MB, and their survival could be promoted by the routine use of G-CSF in children with MB after chemotherapy. However, the function of CD114 in MB tumors is not known. The goals of this proposal are to determine the function of CD114 in MB tumors and to determine whether CD114 could be a target for new types of MB treatment. We propose experiments determine which MB cells express CD114 in MB tumors and how CD114 expression contributes to the growth and survival of CD114-positive MB cells. The results of these studies will increase our understanding of the role of CD114 expression and function in MB tumors and will potentially identify new treatments for children with MB.

Natural Killer Cells for Treatment of Medulloblastoma

Type of Cancer: Pediatric Brain Cancer

Awardees:

• Dan Kaufman, MD, PhD (Moores Cancer Center at UC San Diego Health)
• Robert Wechsler-Reya, PhD (Sanford Burnham Prebys Medical Discovery Institute)

Immunotherapy is emerging as a powerful approach to treating cancer. Most immunotherapies work by increasing the activity of immune cells called T cells, but T cells can only attack tumor cells if the tumor cells display a protein on their surface called MHC-I. In our recent studies of the childhood brain tumor medulloblastoma, we discovered that tumor cells frequently shut off expression of MHC-1, and thereby become invisible to T cells. This raises the possibility that these patients may be insensitive to T cell-based immunotherapy. In contrast, a different type of immune cell called a natural killer cell is not dependent on (and is actually inhibited by) MHC-I, and thus may be better able to kill tumors that do not express MHC-I. In the proposed studies, we will test whether natural killer cells can be used to attack and kill medulloblastoma cells that lack MHC-I. If successful, these studies could markedly increase the numbers of patients who benefit from this type of cell-based immunotherapy.

Transcriptomic and Epigenomic Profiling to Reveal Tumor-Infiltrating Lymphocyte and Microglia Functional Phenotype and Clonality In Pediatric Brain Tumors

Type of Cancer: Pediatric Brain Cancer

Awardees:

• Anusha Preethi Ganesan, MD (Rady Children’s Hospital-San Diego)
• P. Vijayanand, PhD (Ja Jolla Institute for Allergy and Immunology)

Brain tumors are the leading cause of cancer-related mortality in children. Despite medical and surgical advances in cancer treatment, a significant proportion of pediatric brain tumors remain incurable and newer treatments are urgently needed. Numerous lines of evidence support a potentially important role for T cell-mediated immunosurveillance of the CNS in mediating protection against cancer. Immunotherapies that boost the anti-tumor responses of T cells have shown promise in many adult cancers, however translation of their clinical success to pediatric tumors is hindered by a lack of understanding of the tumor immune microenvironment within these tumors. The goal of this project is to define the molecular players and mechanisms involved in anti-tumor immune response in pediatric brain tumors. We will undertake an unbiased and comprehensive approach to define transcriptomic and epigenomic profile of purified tumor-infiltrating lymphocytes (TILs), microglia and other immune cell subsets in a well-characterized cohort of pediatric patients with brain tumors. Utilizing state-of-the-art genomic tools such as single-cell RNA sequencing, ATAC-sequencing and histone ChIP-Seq, we will evaluate the TIL functional phenotype, TCR/BCR sequence and clonality in pediatric brain tumors. In addition, similar analysis in tumor-associated microglia and other key immune cell subsets will unravel their co-regulatory relationship and tumor regulatory mechanisms. Integrated bioinformatics analyses of these datasets will reveal novel immune pathways that may be targeted in immunotherapeutic strategies against pediatric brain tumors.

Targeting a Therapeutic Vulnerability in PTEN-Deficient Brain Tumors

Type of Cancer: Brain Cancer

Awardees:

• Frank Furnari, PhD (Ludwig Institute, UC San Diego)
• Geoffrey Wahl, PhD (Salk Institute for Biological Studies)

Glioblastoma (GBM), the most common primary brain tumor in adults, is a highly invasive neurologically destructive tumor with a survival range of 12-15 months, despite aggressive treatment efforts. Like most cancers, gain of function of oncogenes and/or loss of function of tumor suppressor genes are common in GBM, and in addition to bestowing enhanced growth to the tumor, these genetic alterations create collateral dependencies on cellular processes, otherwise known as synthetic vulnerabilities, that can be targeted for cancer therapy. A gene associated with the aggressive nature of GBM is the PTEN tumor suppressor gene, which is affected in ~40% of patients. This proposal aims to leverage this information by establishing a new molecular-based platform designed to rapidly identify molecules able to inhibit the growth of PTEN-deficient GBMs. By focusing on this genetically distinct class of GBMs, this proposal represents a unique personalized therapeutic approach to target an Achilles heel that arises as a consequence of a specific gene mutation.

Responses of Melanoma Patients to Checkpoint Immunotherapy

Type of Cancer: Melanoma

Awardees:

• Linda Bradley, PhD (Sanford Burnham Prebys Medical Discovery Institute)
• Gregory Daniels, MD, PhD (Moores Cancer Center at UC San Diego Health)

Advances in immunotherapy for cancer have yielded tremendous optimism that even aggressive cancers, including metastatic melanoma, can one day be cured in the majority of patients. However, many patients fail to respond to current treatments, or their tumors become resistant to treatment. It has been proposed that the T cells that are necessary for tumor eradication become refractory to treatment, by the development of progressive loss of function. Thus, there is a critical need to better understand the loss of T cell function in patients and to develop new targets for immune modulation by distinct immune mechanisms. This pilot project is a collaboration between Dr. Linda Bradley in the Tumor Microenvironment and Cancer Immunology program at the Sanford Burnham Prebys Medical Discovery Institute (SBP) and Dr. Gregory Daniels in the Solid Therapeutics program at Moore’s Cancer Center (MCC). We seek to evaluate the responses of melanoma patient T cells to anti-PD-1 blockade, the frequencies of responsive vs non-responsive subsets of T cells, and the potential for blocking a new T cell inhibitory receptor that we discovered, designated PSGL-1, as a new immunotherapy for metastatic melanoma and other cancers.

Research Focus: In Vivo Modeling of Anti- Tumor Responses of Human Melanoma Patients and Their Responses to Checkpoint Immunotherapy

Type of Cancer: Melanoma Cancer

Awardees:

• Linda Bradley, PhD (Sanford-Burnham Prebys Medical Discovery Institute)
• Greg Daniels, MD, PhD (Moores Cancer Center at UC San Diego Health)

Melanoma skin cancer is a deadly disease that kills many patients after the cancer spreads. Current therapies are not effective, and many patients have very few treatment options after metastasis occurs. Recently, immunotherapies have been developed to augment immune cell function to kill tumors. Even though these immunotherapies are effective in some patients, many others are nonresponsive. There is, therefore, a pressing need to predict whether a patient will or will not respond to these drugs so that effective personalized treatment options can be offered. Pedal-funded research will allow scientists to test a patient’s immune system against their tumors to determine whether they will have a productive response with clinically available drugs. These studies will be highly significant because if they show promise in melanoma, these tools can be further applied to combat other cancers in humans.

Inhibiting Liver Cancer Stem Cells to Improve Response to Thermal Ablation

Type of Cancer: Liver Cancer

Awardees:

• Isabel Newton, MD, PhD (UC San Diego Health)
• Nicholas Webster, PhD (Moores Cancer Center at UC San Diego Health)
• Gen-Sheng Feng, PhD (UC San Diego)

Liver cancer, or hepatocellular carcinoma (HCC), is the 5th most common cancer and the world’s 2nd leading cause of cancer-related death in adult men. According to the CDC, it is the only cancer for which the incidence and mortality are rising. An increasingly significant cause of HCC is fatty liver disease, for which obesity is a risk factor. Since 71% of Americans are overweight or obese, the number of HCCs is expected to rise. Surgery offers the best hope for a cure, yet most HCC patients are not surgical candidates. The best alternative is percutaneous thermal ablation, a minimally invasive way to destroy the tumor without surgery. Yet when cancer cells are left behind, HCC can recur. The likely source of recurrence is from treatment-resistant cells called “cancer stem cells” which become stimulated under the stress conditions induced by percutaneous thermal ablation. No current therapies target these cells. Our study proposes to combine niclosamide ethanolamine, an FDA-approved antiparasitic drug that inhibits cancer stem cells, with percutaneous thermal ablation in mice with fatty liver disease that develop HCC. In the short term, this study will improve our understanding of the effect of percutaneous thermal ablation on HCC cancer stem cells in a singularly clinically-relevant model. In the long term, this study has the potential for rapid translation to clinical trials. If successful in improving outcomes after percutaneous thermal ablation, this combined approach with niclosamide ethanolamine could ultimately curb the mortality from HCC and help countless patients.

Research Focus: The GNAS-PKA Onco-Signaling Network in Colorectal Malignancies

Awardees:

• Silvio Gutkind, PhD (Moores Cancer Center at UC San Diego Health)
• Susan Taylor, Ph.D. (Moores Cancer Center at UC San Diego Health)
• Tony Hunter, PhD (Salk Institute for Biological Studies)

Every year, more than 135,000 Americans – and 1.35 million people worldwide – are diagnosed with colorectal cancer. With 50,000 deaths each year, colorectal cancer is the second leading cause of cancer deaths in the United States. New approaches are clearly needed to explain the underlying biology of colorectal cancer, which will help the development of new and more effective options to prevent and treat this highly prevalent human malignancy. Aspirin and multiple over the counter non-steroidal anti-inflammatory drugs are effective in preventing colorectal cancer, supporting that chronic inflammation contributes to the development of this cancer. A molecule known as Protein Kinase A (PKA) is often stimulated by inflammatory mediators in the normal intestine and colorectal tumors. Through PEDAL15 funding, scientists will be able to study what causes the unrestrained activation of PKA in colorectal cancer and how PKA then stimulates cancer growth. It is believed that these studies will increase our understanding of colorectal cancer initiation and progression, will help identify patients at risk of developing this malignancy, and will reveal new therapies to prevent and treat this disease.

Research Focus: Decoding Colon Cancers Using Boolean Principles

Type of Cancer: Colorectal Cancer

Awardees:

• Pradipta Ghosh, MD (Moores Cancer Center at UC San Diego Health)
• Debashis Sahoo, PhD (Moores Cancer Center at UC San Diego Health)
• Manuel Perucho, PhD (Sanford Burnham Prebys Medical Discovery Institute)

Colorectal cancer is the 3rd most common cancer in the US. Despite a large amount of work that has concentrated on understanding colon tumor formation, we still do not know the full complement of molecular lesions that are individually necessary (and together sufficient) to cause colorectal cancer. Neither do we understand why some specific mutations that are relatively rare in other tumors are extremely common in colorectal cancer. As a result, the race toward personalized and precision-based management plan in colorectal cancer has seen a lost decade with little to nothing that has translated to the cancer clinics after the discovery of the impact of tumor micro-satellite instability status in the mid-90’s. Big data (gene expression data sets), meanwhile, has accumulated from multiple studies, but has had a ‘streetlight effect’: where and how we look affects what we see through our own biases. Thus, a lot of what has been accomplished using such big data is justification/ rationalization of research through the same bias-filled traditional reductionist approach [one protein, pathway at a time based on where one wanted to look]. Which can explain why most pre-clinically identified therapeutic target or biomarkers identified at the bench stumble during translation into clinics. Currently, there is no effective way to extract meaningful information from such noisy collection of Big data in an unbiased way.

CLINICAL TRIAL: Low Dose Chemotherapy for Immuno-activation in Lung Cancer

Type of Cancer: Lung Cancer

Awardees:

• Michael Karin, PhD (Moores Cancer Center at UC San Diego Health)
• Hatim Husain, MD (Moores Cancer Center at UC San Diego Health)

Immune checkpoint inhibitors are a new class of drugs that have revolutionized lung cancer treatment across various lines of therapy. The most versatile of this group are antibodies that target molecule on immune cells called checkpoints, namelyPD-1 or its ligand PD-L1. Although effective in many cancer types, response rates to these drugs rarely exceed 30-40% in later lines of therapy, necessitating the search for agents that may combine to work in synergy with checkpoint blockers to increase effectiveness. Using mouse models of cancer, we found that the conventional chemotherapeutic drug oxaliplatin has the unique ability to greatly enhance the response to immunotherapy. Traditional doses of chemotherapy may not be needed when combined with immunotherapy. We will investigate how low doses of chemotherapy may increase an immune response and minimize side effects in a clinical trial. Furthermore, we will investigate lung tumor specimens to find markers that will help us to better understand how we can pair appropriate therapies for patients in the future.

Research Focus: KRAS Addiction and Protein Biomarkers of Response to Anti-KRAS Therapy in NSCLC Patient-derived Xenografts

Awardees:

• Hatim Husain, MD (Moores Cancer Center at UC San Diego Health)
• Garth Powis, DPhil (Sanford-Burnham Prebys Medical Discovery Institute)

In approximately 25 percent of lung cancer cases, the gene KRAS may be mutated. Therapies for patients who have a KRAS mutation are not currently approved by the United States Food and Drug Administration. This challenge remains a largely unmet need among lung cancer patients. Every year an estimated 39,000 people will die of this molecular form of the disease. In this PEDAL-funded project, scientists will study proteins that are expressed in these tumors and seek to identify additional markers that may be used to determine who will respond to novel KRAS-directed therapies. Additionally, the funding will also facilitate the study of new drug therapies developed to target the KRAS protein complex and test its efficacy in KRAS-mutated and pathway dependent cancer cells. This groundbreaking research could serve the basis for a future clinical trial to evaluate a new anti-KRAS drug for patients with KRAS mutations and pathway dependency.

Research Focus: Targeting KRAS Mutant lung cancer with biphosphonated/statins and rapamycin analogs

Awardees:

• Lyudmila Bazhenova, MD (Moores Cancer Center at UC San Diego Health)
• Inder Verma, PhD (Salk Institute for Biological Studies)

Lung cancer is the most common human malignancy and leads to about one-third of all cancer-related deaths. There are three major genetic mutations found in lung cancers: EGFR, EML4-ALK and KRAS. The latter, KRAS, is more common in Caucasians, males, and smokers, and does not currently have good therapeutic options. Previous studies have shown that select drugs prescribed for bone resorption, when used in combination with rapamycin (an immunosuppressant commonly used to prevent the body from rejecting organ and bone marrow transplants), could successfully prevent tumor growth and prolong survival. PEDAL15 grant funding will allow scientists to test the drug combination in metastatic lung tumors with KRAS mutations, as well as decipher what makes a tumor more sensitive to this drug combination. Additionally, it has been found that certain drugs designed to lower blood cholesterol (statins) could also inhibit protein modification. This grant will make it possible for scientists to test combinations of statins with rapamycin. Scientists hope to develop a viable combination therapy to combat lung cancers with KRAS mutations and demonstrate the power of immediate translation of results into the clinic.

CLINICAL TRIAL: Investigating the Efficacy of Radium-223 with Olaparib in Men with Metastatic Castration-resistant Prostate Cancer

Type of Cancer: Prostate Cancer

Awardees:

• Rana McKay, MD (UC San Diego Health)
• Christina Jamieson, PhD (UC San Diego Health)

Metastatic castration-resistant prostate cancer heralds a lethal disease and represents a major unmet need in clinical practice. Despite the confirmed efficacy of approved agents for men with mCRPC, resistance to treatment is universal. Novel treatments and combinations are imperative to improve outcomes for patients. Radium-223, an alpha-emitting radioisotope, has been shown to prolong overall survival in mCRPC2. Studies have demonstrated that enhanced DNA repair is a potential resistance mechanism to radiation and impairment of this process, via PARP inhibitors such as olaparib, can promote cell death and delay tumor growth4·5. We hypothesize that the addition of olaparib to radium-223 will improve survival for patients and outcomes may be dependent on tumor DNA repair status which may serve as predictive biomarker of response. To test this hypothesize, we have designed a phase 1/11 open-label randomized clinical trial of standard of care radium-223 with or without olaparib. To investigate molecular mechanisms of response and resistance to treatment and interrogate molecular aberrations in the DNA repair pathway, patients will undergo a mandatory baseline and optional progression tumor biopsy. Additionally, immunoprofiling of blood and tissue specimens will be performed on a subset of patients to investigate the rationale for combinatorial immunotherapy to radium-223 with or without olaparib. This study has the potential to improve the efficacy of existing treatment options for mCRPC patients. By harnessing vast advances in technology, genetics, and biomedical research, molecular tumor profiling has the potential to better inform patient selection for a given treatment and transform clinical decision-making.

CLINICAL TRIAL: Safety and Feasibility Study of Personalized Immunotherapy in Adults with Advanced Cancers

Type of Cancer: All Cancers

Awardees:

• Ezra Cohen, MD, FRCPSC, FASCO (Moores Cancer Center at UC San Diego Health)
• Stephen Schoenberger, PhD (La Jolla Institute of Allergy and Immunology)
• Aaron Miller, MD, PhD (Moores Cancer Center at UC San Diego Health)

Immunotherapy has produced a paradigm shift in the way we approach and manage cancer. In the last few years we have seen unprecedented improvements in cancer survival stemming from immunotherapy with corresponding expedited drug approvals by the FDA. These agents are generally well tolerated and can have deep and enduring responses once immune recognition of the tumor has occurred. Unfortunately, over 80% of cancer patients do not benefit from current immunotherapies because the available drugs are ineffective at inducing immune rejection of the tumor. Accordingly, we hypothesized that if a patient’s immune system is stimulated to recognize their cancer then a vigorous anti-tumor response can be achieved. Over the last four years, we have developed a method of identifying targets in a patient’s cancer that can be seen by their immune system, so called “neoantigens”. We are now taking this discovery to the clinic by conducting a clinical trial using a personalized neoantigen vaccine in combination with standard immunotherapy. The clinical trial will test the feasibility of creating truly individualized cancer vaccines and demonstrating the efficacy of this approach at inducing immune responses against a patient’s cancer. This study will lay the groundwork for larger trials for patients with metastatic cancer, irrespective of the primary tumor site, and for studies testing the effectiveness of personalized cancer vaccines at preventing cancer recurrence after definitive therapy. This work will usher in a new era of transformational immunotherapy that is precise, tailored to the patient, and with little to no side effects.

Targeting FZD7 in human cancers

Type of Cancer: All Cancers

Awardees:

• Karl Willert, PhD (Moores Cancer Center at UC San Diego Health)
• Dennis Carson, MD (UC San Diego Health)

A major shortcoming of current cancer therapies is lack of specificity. Chemotherapeutic drugs act on fast dividing cells, such as cancer cells. However, cells in normal tissues, such as skin, blood and the gastrointestinal tract, also divide and hence are highly sensitive to chemotherapeutic drugs, resulting in many undesired toxic side-effects and the all-too-common misconception that cancer treatments do more harm than good. Recent advances in immunotherapies overcome many of the issues associated with chemotherapy. With the rapid advances in molecular profiling of human cancers and precision medicine, it is now possible to identify patient-specific mutations in cancers and design specific immunotherapies to block the aggressive growth of these cancers.
We have identified the gene FRIZZLED7 (FZD7) as a molecular marker of many cancer types. With its highly restricted expression pattern—absent in children and adults and present in the embryo and various cancers— FZD7 is an ideal target for immunotherapies. We have developed an antibody that only reacts with FZD7, thus providing us with a molecular handle to identify, target and potentially kill cancer cells. In this application, we propose to leverage our uniquely specific FZD7 antibody to develop highly selective strategies to combat cancers in which FZD7 is highly expressed.
The short-term goals of the proposed research are foundational and basic in nature. Successful completion of this 1-year study will immediately feed into our long-term goals, including clinical development, filing of a new investigational drug (IND) application with the FDA, and initiating a Phase 1 clinical trial.

Evaluation of Carcinogen Exposure via Genome-Wide DNA-Adduct Signatures

Type of Cancer: All Cancers

Awardees:

• Olivier Harismendy, PhD (Moores Cancer Center at UC San Diego Health)
• Ludmil Alexandrov, PhD (UC San Diego)

Multiple organs of the body are constantly exposed to a plethora of carcinogens from exogenous origin (e.g., alcohol, tobacco, pollution), or due to endogenous processes (inflammation, infection), many of which reacts with the DNA. These damages, called DNA adducts, in absence of repair, can lead to somatic mutations and become the primary causes of cancer. Importantly, and similar to what has been observed for tumor mutations, every tissue in every patient likely has a unique set of damages representing a signature of their lifelong exposures and subsequent modeling by cellular processes and inherited genetics. In this project, we will validate and apply a novel genome-wide assay (Ad-Seq) to globally examine the landscape of DNA adducts, ignoring their exact chemistry but rather relying on their genomic location and DNA sequence preference. We will utilize the resulting molecular profiles to predict exposure and compare damages in the DNA of normal tissues to mutations found in the adjacent tumor. This work will establish Ad-Seq profiling as a novel tool to assess personal cancer risk, integrating both environment and genetics, reporting on the global molecular consequences of carcinogens on the DNA. The approach will therefore provide a more direct and richer context to investigate the link between mutagenic exposure and subsequent mutations, leading to more personal prevention and screening strategies.

Inducing Cytosolic Chromatin Fragments in Cancer Cells to Turn Cold Tumors Hot

Type of Cancer: All Cancers

Awardees:

• Jack Bui, PhD (Moores Cancer Center at UC San Diego Health)
• Peter Adams, PhD (Sanford Burnham Prebys Medical Discovery Institute)

Immune therapy is a method to treat cancer using the body’s own immune system. This method works because immune cells such as T cells can infiltrate a tumor mass and specifically destroy cancer cells. For some patients, the T cells can also seek out and destroy cancer cells that have metastasized throughout the body. Additionally, the T cells survive even when the cancer cells have been destroyed and thus can prevent recurrence of cancer. Thus, immune therapy has the potential to produce durable, long-lasting cures for cancer. Unfortunately, not all patients respond to immune therapy. In particular, some patients have “cold” tumors that do not contain many immune cells. These tumors resist immune therapy by preventing the infiltration and/or accumulation of T cells in the tumor mass. This grant seeks to discover new ways to make a cold tumor “hot”. Specifically, we wish to manipulate the cancer cell to force it to make proteins such as cytokines that recruit immune cells. In essence, our research will turn cancer cells into “suicide cells” that act as beacons for anti-tumor immune cells. We envision that our therapy will amplify and broaden the efficacy of current immune therapies and provide long-lasting remissions for a large swath of cancer patients.

Research Focus: Oncogenic Regulation of B-Lymphomagenesis by the Chromatin Modulator DOT1L

Type of Cancer: All Cancers

Awardees:

• Bing Ren, PhD (Moores Cancer Center at UC San Diego Health)
• Aniruddha Deshpande, PhD (Sanford Burnham Prebys Medical Discovery Institute)

The epigenome is an exciting new frontier for therapeutic intervention in human disease because unlike genomic abnormalities that are difficult to reverse therapeutically, abnormal epigenetic changes are amenable to reversal using chemical compounds. Our collaborative proposal aims to identify and characterize a novel, actionable, epigenetic vulnerability in B- lymphomas where safer curative treatment options are needed.

Research Focus: Identification of genes critical for the production of T-cells from human pluripotent stem cells for development of “off-the-shelf” T-cells immunotherapies

Type of Cancer: All Cancers

Awardees:

• Dan S. Kaufman, MD, PhD (Moores Cancer Center at UC San Diego Health)
• Sumit K. Chanda, PhD (Sanford Burnham Prebys Medical Discovery Institute)

While anti-cancer therapies continue to improve, too many patients still do not respond to conventional therapies and die from their malignancy. A promising new therapy involves the use of the patient’s own white blood cells, known as T-cells, being removed and engineered to specifically target tumors before being reintroduced to the patient. While this cancer immunotherapy approach appears to work well for some cancers, it is a laborious and expensive process. An ideal solution is to produce “off the shelf” T-cells, which can be genetically altered to kill tumors. Human pluripotent stem cells can multiply without limit, differentiate into T-cells, and be engineered to avoid being rejected by the immune systems of different patients, making them an ideal source universal donor cells. While previous studies have demonstrated derivation of T-cells from human pluripotent stem cells, the process is inefficient. In this proposal we will use genetic screening to individually disrupt genes in stem cells and then derive specific T-cells capable of killing tumors. We will select these tumor-killing cells and then use DNA sequencing to discern which genes are disrupted in the desired population. These genes can then be studied individually to derive stem cell lines, which will reliably give rise to T-cells capable of killing tumors. These cells can then be modified to both avoid host rejection and target specific tumors. These universal donor “off the shelf” T-cells will then be suitable to treat cancers in multiple patients.

Research Focus: Mechanisms Linking Prolonged Nightly Fasting with Cancer Risk

Type of Cancer: All Cancers

Awardees:

• Ruth Patterson, PhD (Moores Cancer Center at UC San Diego Health)
• Dorothy Sears, PhD (Moores Cancer Center at UC San Diego Health)
• Satchidananda Panda, PhD (Salk Institute for Biological Studies)

Obesity is an epidemic. Identification and validation of feasible, effective approaches to reducing obesity-related cancer risk are needed. Research studies indicate that time-restricted feeding can protect against obesity, high insulin levels, fatty liver, and inflammation – all of which can increase cancer risk. Through this PEDAL15-funded study, researchers will test whether, in comparison to a short fasting interval, a 13-hour or greater nightly fasting interval is associated with lower blood glucose levels, lower inflammation, lower levels of obesity, and improved sleep. Scientists will also investigate the association of prolonged nightly fasting with metabolites in the blood, such as sugars and fats, and the association of nightly fasting with the gut microbiome (a collection of all microorganisms and viruses that live in the intestines). If habitual prolonged nightly fasting improves metabolic health and reduces obesity-related cancer risks, this would be a crucial discovery in the prevention of cancer in adults.

Research Focus: Targeting Stem Cell Signals in Cancer Development & Progression

Type of Cancer: All Cancers

Awardees:

• Tannishtha Reya, PhD (Moores Cancer Center at UC San Diego Health)
• Michael Jackson, PhD (Sanford Burnham Prebys Medical Discovery Institute)

To identify new therapeutic targets for cancer, researchers have focused on stem cell programs that are reactivated in cancer. It has been demonstrated that the stem cell signal Musashi (Msi) is highly upregulated during leukemia development and that its blockage can prevent tumor growth and progression. Data suggests that targeting Msi may provide a new strategy for therapy. To move this work forward to the clinic, PEDAL15 grant funding will be used to develop inhibitors of Msi and test their effectiveness against cancer growth. Outcomes from this study have the potential to identify a new class of therapeutics for cancers that are largely unresponsive to current therapies.

Research Focus: Detecting Correlates of Vaccine Responses in Allogeneic Hematopoietic Stem Cell Transplant Recipients

Type of Cancer: All Cancers

Awardees:

• Randy Taplitz, PhD (Moores Cancer Center at UC San Diego Health)
• Shane Crotty, PhD La Jolla Institute for Allergy and Immunology

Vaccines decrease the risk of infection by working with the body’s natural defenses to develop immunity or protection against disease. Patients with cancer and other diseases affecting the immune system may lose immunity to those diseases against which they have previously been vaccinated and also may have reduced ability to develop immunity to a new vaccination. Hematopoietic cell transplant (HCT) is a procedure that replaces defective or damaged cells in patients whose normal blood cells have been affected by cancer. PEDAL15 funds will allow scientists to measure vaccine-specific immunity before and after vaccination with the pneumococcal and Tdap vaccines, which are given at standardized times in the year after HCT. Ultimately, this effort is expected to lead to better vaccination strategies which will, in turn, lead to decreased infections due to vaccine-preventable diseases in this vulnerable patient population, as well as contribute to our understanding of immune recovery after HCT.

Research Focus: Highly selective, synthetic, cleavage specificity- based nanobiosensors for tumorigenic and anti- tumorigenic MMPs

Type of Cancer: All Cancers

Awardees:

• Alex Strongin, PhD (Sanford-Burnham Prebys Medical Discovery Institute)
• Shu Chien, MD, PhD (Moores Cancer Center at UC San Diego Health)

There is a consensus among professionals that matrix metalloproteinases (MMPs), the specialized enzymes produced in cancer, are a promising drug target. Despite the urgent need and significant value for cancer patients, MMP biosensors are currently unavailable. As a result, physicians are blindfolded and incapable of selecting optimal treatment regimens for patients. To overcome these deficiencies, researchers will now be able to test the unique fully-synthetic nanobiosensors which allow the read-out of the individual MMPs in cells/tissues.

As a result of this work, clinicians will be armed with a multitude of novel diagnostic/prognostic molecular tools, which can then be used to rationally design a knowledge-based personalized medicine treatment for the individual patients.

Research Focus: Stopping Cancer Growth

Type of Cancer: All Cancers

Awardees:

• Seth Field, MD, PhD (Moores Cancer Center at UC San Diego Health)
• Michael Jackson, PhD (Sanford-Burnham Prebys Medical Discovery Institute)

The process of secretion by which cells export proteins was not previously known to play an important role in cancer. However, a newly discovered pathway that functions in secretion, named for its key protein GOLPH3, drives a high fraction of cancers that together account for the majority of cancer deaths, making an unprecedented link between secretion and cancer. Seth Field, MD, Ph.D., (UC San Diego) and Michael Jackson, Ph.D., (Sanford-Burnham) will collaborate on research to take advantage of this unique pathway as a target for a new class of cancer treatments. They will identify inhibitors of the GOLPH3 pathway to study their potential as novel cancer drugs.