Pancreatic cancer will soon become the second biggest cause of death from cancer in the United States. Patients usually find out they have this disease after it is too late for surgery. This leaves treatment as the only option, and the ones in use only help patients live for a few months. To change this, we need to find new approaches to improve the survival of our patients.
Pancreatic cancer is hard to treat for many reasons. A key issue is that the tumors are made up of many cell types, not just cancer cells. Over the past few years, we have found ways these different cells can act together within a tumor to help cancers grow or avoid therapy. Most recently, we discovered that cancer growth can be slowed by blocking exchange of the amino acid asparagine when their mitochondria are stressed.
The goal of this project is to show how cancer cells make and share asparagine. Knowing this, we can better target this metabolism to kill the cancer cells. From our previous work, we also predict this strategy will help patients better respond to immunotherapy. The results from this project will show us how to improve pancreatic cancer treatment and provide data we need to start new clinical trials.
Immunotherapy has transformed cancer therapy and positively impacted the lives of many patients. However, despite these advances, there remain barriers to the success of immunotherapy, and a majority of patients do not get better from immunotherapy. Unfortunately, soft tissue sarcomas are among the cancers which do not respond well to current immunotherapies, and the survival rate for these rare and difficult-to-treat cancers has barely improved for many years. Therefore, more research is needed to extend the benefits of immunotherapy to sarcoma patients.
The past decade has witnessed a big increase in research on natural killer (NK) cells. NK cells are a part of the immune system and are able to rapidly attack bacteria and cancer cells. Despite their ability to kill tumor cells, success with NK cells in cancer patients has hit roadblocks, in part because these cells lose killing capacity quickly, likely so the body can control them. This proposal seeks to understand how this exhaustion of NK cells can be overcome to better fulfill the promise of NK immunotherapy. We will block a novel receptor (TIGIT) on NK cells since this receptor is consistently upregulated on NK cells. We will use a diverse approach, including mice and human sarcoma samples. Then, we will pilot our new immunotherapy approach using NK cells and TIGIT blockade to release the brakes in a first-in-dog clinical trial for dog patients with soft tissue sarcomas. Cancer is a leading cause of death in dogs, as it is for humans.
Funded in partnership with the Cancer Research Institute through the V Foundation’s Virginia Vine event and Wine Celebration Fund-A-Need
Acute Myelogenous Leukemia (AML) is a cancer that is marked by the uncontrolled growth of immature cells of the myeloid lineage. Current therapies are often not effective, with therapy-resistant cancer cells leading to relapse and death in many patients, including both children and adults. Our goal is to develop a biologic that can block the growth and progression of myeloid leukemias. In previous work, we identified the cell surface protein Tetraspanin3 (Tspan3) as a key new regulator of AML, and showed that its inhibition led to a block in AML growth and improved survival in preclinical models. These data, as well as the successful antibody-mediated targeting of CD20, a tetraspanin-like molecule, provided a strong rationale for developing therapeutic monoclonal antibodies (mAbs) against Tspan3. Importantly, in conjunction with a CRO specializing in antibody development for biotech and pharma, we recently generated mAbs against Tspan3 that block the growth of human leukemia samples in vitro and in preclinical models in vivo. These highly promising data suggest that the antibodies we developed may be effective new therapeutics for targeting myeloid leukemia. To move this work forward towards the clinic, we now propose to determine if biomarkers can be identified to stratify patients for responsiveness to Tspan3 mAbs, develop a response signature to evaluate target engagement, and optimize the antibodies for use in human clinical studies. These studies are important because they have the potential to identify a new class of therapies for cancers that are largely unresponsive to current therapies.
Funded in partnership with the Cancer Research Institute through the V Foundation’s Virginia Vine event and Wine Celebration Fund-A-Need
Cancer immunotherapies have led to major treatment breakthroughs for a number of different cancers, but the majority of head and neck cancer patients do not respond to immunotherapies, and clinical responses are often not durable. Excitingly, we have demonstrated that targeting aberrant signaling networks in head and neck cancers can also influence anti-cancer immunity, supporting the development of novel, precision immune oncology therapies that significantly improve response profiles. The research outlined in this proposal will combine treatment with a targeted precision therapy – a highly selective anti-HER3 antibody – possessing both direct tumor and immune microenvironment activity, with PD-1 inhibitor immunotherapy. Leveraging our tobacco-signature oral cavity squamous cell carcinoma mouse model, we have obtained strong preliminary results supporting that our therapeutic combination – anti-HER3 + anti-PD-1 – 1) abolishes cancer-driving signaling pathways, 2) reverses the immunosuppressive microenvironment, and 3) potentiates existing antitumor immunity to achieve durable response. In order to develop more effective multimodal immune-oncology therapies that achieve durable response, we propose to employ several innovative techniques with single-cell level resolution to study the tumor-intrinsic effects of targeted HER3 blockade and how these changes ultimately invigorate and synergize with immunotherapies. Our novel approach represents a paradigm-shift in the design of cancer therapies – one in which therapies are rationally selected to target not only specific oncogenic pathways but also to activate cancer immunosurveillance. The proposed studies will provide the first signal-transduction based multimodal precision immunotherapy for head and neck cancer.
Even if cancer therapeutics and cures were found, they may not benefit African Americans and other under-represented minorities, due in part to a lack of participation in clinical cancer trials and cancer disparities research. Los Angeles has the seventh largest population of Blacks in the United States. Although many may think this population is homogeneous, there are still differences among individuals who identify as Blacks in Los Angeles. This population includes not only individuals born in the U.S. of African ancestry, but also foreign-born including of African or Afro-Caribbean origin. If we are to truly achieve “Victory over Cancer”, under-represented minorities, including all segments of the African American community need to engage in the research process. This grant will allow for holding focus groups with various segments of the AA community, achieving a greater understanding of barriers to CT and acceptance of precision medicine research. We will be able to obtain information for the creation of an outreach and awareness raising tool kit to work with AA community leaders, faith based and other organizations, in advancing knowledge and changing attitudes towards CT participation, provision of biospecimens and inclusion of AA communities in cancer disparities research.
With an extensive cohort of gastric cancer genomic data, there are many new avenues for translational research and clinical investigations. Importantly, a registry this size provides significant degree of statistical power, thus providing researchers with an invaluable resource. Researchers and clinicians in any discipline and at any institution across the world may access this data for independent discovery and validation studies. For example, an investigator may access the data to answer the question, “I found that H. pylori infected patients often have downstream functional mutation in the gene MUC1; can this finding be replicated in another patient population?” The end results may be a new practical and scalable early detection technology, or a precision therapy for gastric cancer patients. Ultimately, the GCR is designed to be a resource for accelerating gastric cancer research.
FUNDED BY THE STUART SCOTT MEMORIAL CANCER RESEARCH FUND WITH SUPPORT FROM BRISTOL MYERS SQUIBB
For a patient with a blood cancer that has not responded to standard treatment, an allogeneic hematopoietic cell transplant (allo-HCT; also referred to as bone marrow transplant) provides the potential for a cure. However, there is still the possibility that the patient’s disease may relapse. Another potential risk of allo-HCT may result when the immune cells from the bone marrow see the recipient as foreign, leading to a complication called graft versus host disease (GVHD). In this approach, I will investigate the use of an allo-HCT followed by donor immune cells targeted to kill the tumor, CD19-targeted chimeric antigen receptor (CAR) T cells. Additionally, to improve the safety of the donor T cells I will utilize genetic engineering with CRISPR/Cas9 to remove the T cell receptor. Hence, I will also evaluate the functional and mechanistic impact of this genome engineering on the immunometabolism of the T cells.
FUNDED BY THE STUART SCOTT MEMORIAL CANCER RESEARCH FUND WITH SUPPORT FROM BRISTOL MYERS SQUIBB
For the past 20 years, the number of people under the age of 50 who are diagnosed with colon and rectal cancer has been rising very quickly, especially among Latinos living in the US and in Mexico. In fact, it is predicted that in the next 10 years, 1 in 10 colon cancer cases, and 1 in 4 rectal cancer cases will be in people younger than the age of 50. Currently, very little is known about the reasons behind this. We think that the food we eat, and our behaviors may play a role in getting colon and rectal cancer. We also think that the type of bacteria in our gut may predispose certain people to getting cancer at a younger age.
In order to explore this, we plan to invite 90 people in California and Mexico City, who identify as Latino, and who were younger that 50 when they were diagnosed with colon or rectal cancer to participate in our study. We will ask them to collect one stool sample at home, and will study the bacteria in that sample as well their tumors. We will also collect detailed information about the foods they eat, and their background using surveys. Overall, we hope to gather very important information that could help us understand why colon and rectal cancer is on the rise among younger people. This information could also help us identify new ways of preventing colon and rectal cancer in the future.
One in every eight women will be diagnosed with breast cancer in a lifetime. But it doesn’t impact everyone equally. While Caucasian women are more likely to be diagnosed with breast cancer, African- American (AA) women are more likely to die from the disease. In addition, AA women are more likely to be diagnosed at a younger age and have a more aggressive form of breast cancer. There have been many improvements in the treatment of breast cancer leading to a lower chance of dying from the disease. But AA women have not been shown to benefit as much as Caucasian women from these advancements. There are many factors believed to be the reason for this racial difference in survival. But there is a need for more research into this area. One way to better study these factors is within the context of a clinical trial. AA women are historically less likely to be in a cancer clinical trial study. This proposed study is aimed at increasing the enrollment of AA female breast cancer patients in clinical trials at UCSD by creating a clinical trial education program to both educate and engage the community. This is predicted to lead to a decrease in the current breast cancer survival disparity.
Gastric cancer is the fifth most frequently diagnosed malignancy in men and women, with nearly 800,000 deaths per year, making it the third leading cause of cancer related death worldwide.Therefore, it is critical to find more effective therapeutic approaches for this disease. Our group has investigated the molecular make up of gastric cancer using large patient cohorts to better understand the differences of molecular markers in gastric cancer and to identify new targets for drug development. Our research was able to find one of the main regulator of tumor growth and spread. This genetic alteration is called lysine methyltransferase 2 (KMT2) which is frequently altered in gastric cancer and a key driver of tumor growth.When normal tissues loses this gene, this tissue can became cancerous by promoting the development of tumor cells. Our group (Wang J, et al., JCO, 2020) was one of the first working on this particular gene and has recently conducted a comprehensive analysis of 1,245 patients with advanced gastric cancer, whose tumors were analyzed using with comprehensive and cutting edge molecular testing technologies. We found that patients with the KMT2 mutation have very unique tumor characteristics such as changes in the DNA repair pathways which makes them very vulnerable to specific chemotherapeutic drugs but also novel targeted therapies. Our project focuses onstudyingwhat the best treatment therapies for this uniquely subgroup of gastric cancer patient will be and explore existing and novel agents to improve outcome in patients with gastric cancer. The goal is that our project will lead to more effective and less toxic treatment options for patients with gastric cancer.
