“Understanding and Overcoming HNF1A- Driven Drug Resistance in Pancreatic Cancer,” led by Ethan Abel, PhD, Department of Molecular and Cellular Biology
Pancreatic cancer is one of the most lethal cancers because there are few treatments that are effective against it. With the help of this grant award, a new study will explore how a poorly understood protein called HNF1A promotes this cancer’s resistance to drugs targeting the protein KRAS, which is believed to drive more than 90% of all pancreatic cancers. It will also determine whether drugs called BET- inhibitors could improve the effectiveness of current treatments and save more lives from this deadly disease.
“Selective Synthetic Lethality Strategy for p53-Deficient Breast and Pancreatic Cancers,” led by Andrei Bakin, PhD, Department of Cancer Genetics and Genomics
Metastatic breast and pancreatic cancers are among the leading causes of cancer death in the United States. This study will investigate the effectiveness of a two-drug combination that has never been tested before. It will selectively target breast and pancreatic cancers that have a genetic alteration in a tumor suppressor called p53. With the data generated, researchers can launch a phase 1 clinical trial to test this new regimen, with the goal of improving patient outcomes and saving more lives from these devastating diseases.
“Novel Interactions at the Cell Membrane of the GTP Biosynthetic Enzyme Inositol Monophosphate Dehydrogenase 2 (IMPDH2) Control Tumor Invasiveness,” led by Anna Bianchi-Smiraglia, PhD, Department of Cell Stress Biology
Triple negative breast cancer (TNBC) is an aggressive type of cancer, with high incidence of metastatic progression. Understanding how tumors escape the primary cancer site to form distant lesions will help begin to prevent this spread. Roswell Park researchers have discovered a fundamental connection between the metabolism of GTP — a building block of our nucleic acids — and the metastatic process. This grant will allow for close investigation aimed at understanding how a rate-limiting enzyme for GTP production supports invasion, with the ultimate goal of developing novel ways to prevent deadly metastasis.
“Targeting Metabolic Enzyme PFKFB4 in Triple Negative Breast Cancer,” led by Subhamoy Dasgupta, PhD, Department of Cell Stress Biology
Unfortunately, there are currently no targeted therapies for TNBC patients, and the majority patients become resistant to chemotherapy. Researchers have detected a cancer-specific energy-generating enzyme that is very active in aggressive TNBC. When this enzyme activity is elevated, TNBC patients experience the worst outcomes of recurrence and metastasis. If we find strategies to inhibit this powerful metabolic enzyme, we can potentially discover new ways to combat TNBC recurrence or metastasis.
“Mobilizing the Immune System to Reduce the Need for Chemotherapy and Improve Outcomes in Triple Negative Breast Cancer,” led by Shipra Gandhi, MD, Department of Medicine
We know that TNBC patients who have no remaining signs of cancer after their first treatment regimen (known as pCR, or pathologic complete response) have improved survival rates overall. But they only comprise 25%-35% of TNBC patients. Through a phase 1 clinical trial, we will test a new combination of medications that we believe will produce an increased rate of pCR, better prognoses and decreased need for more intensive chemotherapy. The results will enable us to pursue national grant funding that will allow us to conduct further clinical trials of this drug combination.
“Reactivating p53 Mutants for Cancer Treatment by Targeting PEPD,” led by Yuesheng Zhang, MD, PhD, Department of Pharmacology and Therapeutics
One of the factors determining how tumors grow is a protein known as the cellular gatekeeper: p53 tumor suppressor. But it also is frequently mutated and either is inactivated or becomes a tumor promoter in cancer, including 65%-85% of TNBCs. Researchers seek to shed light on how another protein, known as PEPD, could be used to trigger mutated p53’s tumor-suppressing actions. This research could revolutionize understanding of the biology and regulation of p53 mutants, identify a novel therapeutic strategy in cancers and generate data important for obtaining national funding for further research to develop PEPD-based therapeutic strategies in cancer.
“Investigating the Role of Breastfeeding in Preventing Aggressive Breast Cancer,” led by Michael Higgins, PhD, Department of Molecular and Cellular Biology
Black women who develop breast cancer have poorer prognoses than white women with the disease and are more likely to develop estrogen-receptor negative (ER-) breast cancer, which is harder to treat. This may be partly due to having multiple children and a lower rate of breastfeeding, which could result in abnormal cells accumulating in breast tissue. The hypothesis is that when these cells become cancerous, they will develop into ER- breast cancer. The results will reinforce education initiatives and hopefully lead to new preventative measures for women who don’t breastfeed.
“Racial Differences in the Interactions Between Tumor Cells and Immune Cells in Breast Cancer,” led by Angela Omilian, PhD, Department of Cancer Prevention and Control
Black women with breast cancer have more aggressive tumors and poorer survival rates than white women. Because women of African descent have stronger immune responses, researchers hypothesize that their own immune systems select for more aggressive breast tumors due to a process called immunoediting. Researchers will evaluate how immune cells interact with tumor cells and compare this in black and white women. The findings will show how a patient’s immune environment influences tumor development and progression, and may also inform treatment strategies for both black and white women.
“I am excited that this project was selected for funding by the Roswell Park Alliance Foundation and wish to thank the donors for their generous support. Previous funding by the Foundation made it possible for me to successfully compete for funding from the National Cancer Institute and has allowed me to pursue promising research leads.”