Nearly all of the FDA-approved therapies in the last decade for bladder cancer target cell surface proteins. Despite enormous progress in targeted therapy development, however, only five unique targets (out of thousands) have been explored. In addition, because current tumor targets are often also expressed on normal tissues, toxic side effects are common and can even be life-threatening. Therefore, identifying cancer-specific, targetable proteins is critical to enhancing efficacy and safety of bladder cancer drugs. In this project, Dr. Chou will utilize a new technique to identify novel drug targets from patient tumor samples, develop molecules that bind them, and engineer these molecules into cellular therapies. He will also evaluate a strategy to target a surface protein called CDCP1 and explore the role of several proteases (enzymes that break down proteins) in therapy resistance. Dr. Chou hopes that his work will reveal a new class of targetable surface proteins for bladder cancer and pave the way for future clinical trials.

Hepatocellular carcinoma (HCC), a type of liver cancer often caused by liver disease related to viral infections or metabolic disease, is a leading cause of cancer deaths globally. Treating HCC with immunotherapy and targeted therapies shows promise, but liver damage can make these treatments challenging to administer and less effective. Dr. Keenan’s preliminary data suggest that certain immune cells, known as myeloid cells, become suppressive in patients with HCC and worsen liver function. However, it is possible that the correct combinations of immunotherapy treatments could partially reverse this myeloid cell suppression and result in better outcomes for patients with HCC. Dr. Keenan will focus on understanding exactly how liver disease affects the immune system and finding ways to counteract the suppressive effects of myeloid cells. By studying blood samples and liver tissues from patients with HCC undergoing immunotherapy treatment, she aims to identify the best combinations to enhance the immune system’s ability to fight liver cancer. This research could lead to new, more effective treatments for patients with liver cancer, potentially improving survival rates and quality of life.

Pancreatic cancer is a highly lethal disease with relatively few treatment options. A new class of inhibitors that target the KRAS gene, which is altered in approximately 90% of pancreatic cancer patients, are showing great promise in the clinical setting as a new therapeutic option for these patients. However, nearly all patients develop resistance and experience tumor regrowth after a relatively short period of treatment with these drugs. Dr. Raghavan aims to investigate how cancer cells adapt and become resistant to these KRAS inhibitors and develop combination therapies to overcome this resistance. He anticipates that these studies will uncover fundamental mechanistic insights into cancer drug resistance and identify novel therapeutic strategies that will improve outcomes for patients with pancreatic cancer.

T-cell engaging bispecific antibodies, which bring T cells close to tumor cells and induce them to kill the tumor cell, are a new class of immunotherapy that have demonstrated efficacy in lymphoma and myeloma and are now in development for many other cancers. In diffuse large B cell lymphoma, bispecific antibodies have proven very effective, but approximately 60% of patients derive no long-term benefit. Dr. Shree is working to understand the requirements for generating an effective bispecific antibody response in patients. This knowledge could result in novel improved treatment approaches for patients with lymphoma and inform the design of bispecific T cell-engaging strategies for other types of tumors.

The goal of Dr. Miller’s research is to determine how mutations in blood cells give rise to pre-malignant blood conditions such as clonal hematopoiesis (CH), which drive the development of blood cancers. To this end, Dr. Miller will study patients with rare inherited diseases and use experimental models in the laboratory. He ultimately seeks to use the data generated through this research to develop new strategies to predict, prevent, and treat highly lethal blood cancers.

Only up to 20% of patients with advanced ovarian cancer will survive five years after diagnosis. This is largely due to the cancer’s resistance to traditional chemotherapy and the current lack of targeted therapies that work with chemotherapy to improve response. Dr. Mullen’s lab has identified a new target, COP9 Signalosome Subunit 5 (COPS5), to treat ovarian cancer. Her team has found that inhibiting COPS5 with a drug called CSN5i-3 drastically improves ovarian cancer response to chemotherapy. She now aims to test the effectiveness of CSN5i-3 and chemotherapy against patient-derived, therapy-resistant ovarian cancer tumors. She will also investigate the mechanism of COPS5, believed to be involved in the repair of DNA damage caused by chemotherapy. Dr. Mullen hopes this innovative target will transform the care of patients with ovarian cancer.

Dr. Weeks [Damon Runyon-Timmerman Traverse Clinical Investigator] plans to develop computerized models that can review images of blood cells and predict a patient’s risk of developing acute myeloid leukemia. Because computers can capture small changes in images better than humans looking at cells under a microscope, such a model could connect data about the shapes and appearance of blood cells to the presence of pre-leukemia genetic changes known as clonal hematopoiesis. This work will inform the extent to which blood cell appearance is associated with the underlying biology of leukemia and Pre-leukemia. Ultimately, Dr. Weeks aims to refine existing models of leukemia risk prediction and pave the way for screening programs that can identify individuals with clonal hematopoiesis who are at the highest risk for progressing to cancer.

Gene expression is a complex process, and sometimes mistakes are made, resulting in the generation of aberrant or “junk” RNAs. Dr. Insco previously discovered that cellular failure to “clean up” this junk RNA can contribute to the development and progression of melanoma. Her work is now focused on targeting aberrant RNA to treat cancer. First, she will identify compounds that specifically target melanomas that are unable to clean up their junk RNAs. Second, she will investigate how immune cells can be activated to attack melanoma cells that have high levels of aberrant RNAs. Many advances in our understanding of RNA biology over the last four decades have resulted in new therapies for patients. As this area of RNA biology is almost completely unexplored, Dr. Insco anticipates that studying mechanisms of aberrant RNA oncogenesis will reveal new therapeutic strategies for patients.

Histologic transformation, when a cancer’s features shift dramatically and it presents as a new cancer type, can occur at any point in the course of disease or arise due to the selective pressure of cancer therapies. One of the most well-recognized examples of histologic transformation is the transformation of follicular lymphoma, a slow-growing cancer of the lymphocytes, to an aggressive lymphoma, typically a large B-cell lymphoma. Despite this being well-recognized in the clinic, understanding of the molecular changes that trigger this transformation remains limited. Dr. Parry seeks to comprehensively study the genetics underlying follicular lymphoma transformation with a goal of improving future recognition and diagnosis of transformation. She also aims to identify unique potential therapeutic targets associated with follicular lymphoma transformation.

New therapeutic approaches are urgently needed for children suffering from high-risk medulloblastoma, a form of pediatric brain cancer, where half of children will experience disease relapse leading to death. Dr. Prensner’s [Ben and Catherine Ivy Foundation Clinical Investigator] work is focused on understanding the biological underpinnings of high-risk medulloblastoma and developing new treatment options. His team recently found that high-risk medulloblastoma may exploit an imbalance in the production of proteins from the tumor cell genetic material (RNA, DNA). Dr. Prensner aims to define the cancer biology that causes an imbalance in the protein-RNA ratio in medulloblastoma, and investigate specific therapeutic options that may target this biology. His hope is that this work leads to new options for clinical trials for children with high-risk medulloblastoma.

Pancreatic cancer is a devastating disease with limited treatment options. New strategies are urgently needed, but few actionable therapeutic targets are known. By systematically testing diverse molecules against pancreatic cancer cells combined with gene knockout studies, Dr. Corsello [Leslie Cohen Seidman Clinical Investigator] has identified a starting point to simultaneously activate inflammatory signaling and cell death pathways. He will determine the efficacy and underlying molecular mechanism of this approach, and potential immunotherapy combinations, using patient-derived tumor models. His goal is to accelerate the development of more effective and less toxic therapies for pancreatic cancer.

Chimeric antigen receptor T cell (CAR T cell) therapy, in which a patient's own immune cells are engineered to target their cancer, has changed the treatment landscape for many blood cancers. Despite promising early results, however, long-term follow-up has revealed that nearly half of patients treated with CAR T cells eventually experience cancer recurrence. Using a variety of techniques in cell lines and patient samples, Dr. Singh [Bakewell Foundation Clinical Investigator] aims to understand how interactions between engineered T cells and blood cancer cells in some cases lead to long-term remission, and in others to therapeutic failure. The broad goals of his lab are to understand the biological signals that cause these therapies to fail, and to use this knowledge to design next-generation immunotherapies that can cure more patients.

Pancreatic cancer develops in the midst of intense scarring and fibrous connective tissue (fibrosis). The architects of this scarring are cells called fibroblasts, known to fuel cancer growth and promote treatment resistance. Dr. Delitto's research is focused on the interface between cancer-induced fibrosis and the immune system. He has shown that fibroblasts play a significant role in shielding cancer cells from immune cells. By altering how fibroblasts sense tissue damage, Dr. Delitto has uncovered a mechanism that reactivates the immune system to fight the tumor. He aims to further develop these findings into a novel immunotherapy regimen for pancreatic cancer.