SIP awards $2.1M in cancer research grants

Research related to breast, pancreatic and brain cancers are among the eight projects that will benefit from $2.1 million in new grants announced by Siteman Cancer Center through its Siteman Investment Program. The goal of the grants is to support and accelerate the pace of innovation in cancer research.

The money awarded comes from a variety of sources: Pedal the Cause annual bike challenge and Illumination gala, through the Cancer Frontier Fund at the Foundation for Barnes-Jewish Hospital; the Fashion Footwear Association of New York; the National Cancer Institute; and the Barnard Trust.

The research projects are described below.

Title: The role of ZFHX4 in the glioblastoma tumor propagating cell state

Principal investigator: Milan Chheda, MD, an assistant professor of medicine at Washington University School of Medicine and a research member of Siteman Cancer Center 

Goal: To understand how a gene, ZFHX4, contributes to the treatment-resistant state of glioblastoma. The information will help the researchers develop new treatments for brain tumors 

Description: Glioblastoma is the most common and aggressive primary brain tumor. A major problem is, despite therapy, the cancer inevitably and quickly recurs. The researchers have identified a gene, ZFHX4, which is required for this treatment-resistant state of glioblastoma cells. They will dissect the possibilities of how ZFHX4 does this. Their studies will test how ZFHX4 operates in patient tumors, how it responds in the setting of treatment and whether it works alone to cause brain tumors or cooperates with other genes. These findings will help them understand how to better target and kill the most treatment-resistant cells in these devastating brain tumors.

Title: Antipsychotics and Breast Cancer 

Principal investigator: Tahir Rahman, MD, an associate professor of psychiatry at Washington University School of Medicine and a research member of Siteman Cancer Center

Goal: To gather and analyze a large data set of women who have taken antipsychotic and mood-stabilizing drugs, to determine which drugs are associated with an increased rate of breast cancer 

Description: Breast cancer is the most common cancer among women in the U.S. Medications called antipsychotics and mood stabilizers are used to treat millions of patients worldwide for mental-health issues such as mood disorders and psychosis in girls and women. Antipsychotic drugs often artificially raise levels of a naturally occurring hormone called prolactin in the body. High prolactin levels have been linked to the development of breast cancer in some studies. This study will examine millions of women who have taken antipsychotic and mood-stabilizing drugs to determine which drugs are associated with an increased rate of breast cancer. The results of this study will allow doctors to make better treatment guides to protect girls and women from developing breast cancer.

Title: Obesity as an obstacle to cancer immunotherapy

Principal investigator: Ryan Teague, PhD, an associate professor of molecular microbiology and immunology at Saint Louis University School of Medicine and a research member of Siteman Cancer Center

Goal: To understand how obesity influences immunotherapy treatment outcomes for cancer patients and to provide fresh insight for improved treatment options for all patients 

Description: More than a third of Americans are considered obese, a condition associated with impaired immunity and a higher risk of cancer. But cancer treatments have changed dramatically in recent years, shifting toward strategies of immunotherapy that rely on boosting a patient’s own immune system to fight cancer. The researchers hypothesize that obesity limits the success of immunotherapy, a hypothesis supported by research in their lab and others. Whether obesity influences outcomes in cancer patients remains unclear and has been mired by conflicting clinical results. These inconsistencies have contributed to the controversial “obesity paradox,” which suggests that obesity has a neutral or even positive impact on patient outcomes, but this idea has come under intense scrutiny. The researchers have proposed new mechanistic studies and complementary analysis to demystify this controversy and provide fresh insight for improved treatment options in all patients.

Title: Using Arginine Metabolism to Treat Sarcomas

Principal investigator: Brian Van Tine, MD, PhD, an assistant professor of medicine at Washington University School of Medicine and a research member of Siteman Cancer Center

Goal: To test a therapy based on cancer cell metabolism that causes tumor starvation in a clinical trial in rare tumors called sarcomas

Description: The goal of this proposal is to test a therapy based on cancer cell metabolism that causes tumor starvation in a clinical trial in rare tumors called sarcomas. Arginine is a crucial building block needed by both normal and cancerous cells. While normal cells can make their own arginine, researchers have discovered that sarcomas do not have the ability to make their own. As a result, when researchers use a drug that destroys arginine in the bloodstream, they are able to selectively starve tumors, as normal cells are able to make arginine and survive. They have found that when tumors are in this starvation state, they are more responsive to chemotherapy. Therefore, the researchers propose to test this finding in a phase II clinical trial in sarcoma patients. In addition, they will continue to study the effects of arginine starvation in the laboratory-based models. Taken together, they will harness these unique findings in tumor metabolism to improve the care of sarcoma patients.

Title: Role of PrimPol in BCRA1-deficient tumors

Principal investigator: Alessandro Vindigni, PhD, a professor of biochemistry and molecular biology at Saint Louis University School of Medicine and a research member of Siteman Cancer Center 

Goal: To study how ovarian cancers carrying BRCA1-gene mutations cope with chemotherapy treatment preventing cell death and, ultimately, to develop a new strategy for chemotherapy

Description: Mutations in the BRCA1 gene are associated with several forms of cancer, including breast and ovarian cancers. Cancer patients carrying BRCA1-gene mutations often are treated with chemotherapeutics that damage the cancer cell’s DNA in the attempt to stop replication and induce cancer cell death. To better mimic chemotherapy in patients, the researchers developed an approach to treat cancer cells with multiple doses of DNA-damaging chemotherapeutics to understand how cancer cells respond. In doing so, they found that BRCA1-mutant cancer cells can adapt to these multiple-drug doses by turning on a rescue pathway as a last resort to protect their DNA replication and prevent cell death. This pathway relies on a specialized protein, called PrimPol, and is activated in BRCA1-mutant cancer cells, but not in normal cells. The goal of this project is to define how this rescue pathway works and to provide a new strategy to sensitize BRCA1-deficient tumors to chemotherapy drugs by preventing cells from using this rescue pathway.

Title: Imaging PARP levels to predict DNA-damaging agent treatment responses in pancreatic cancer

Principal investigators: Delphine Chen, MD, an associate professor of radiology, and Andrea Wang-Gillam, MD, PhD, an associate professor of medicine, both at Washington University School of Medicine, and both research members of Siteman Cancer Center 

Goal: To develop a new positron-emission tomography (PET) imaging tool to more accurately identify when pancreatic cancers would benefit from the addition of a PARP inhibitor (an emerging anticancer therapy) to standard chemotherapy

Description: Pancreatic cancer has poor treatment outcomes due to the fact that nearly all patients develop chemotherapy treatment-resistant disease. Imaging methods that can help study the causes of treatment resistance and provide information regarding what type of therapy could help overcome the treatment resistance could lead to transformative advances in treating this disease. We propose developing a new PET imaging tool to image the expression of PARP, a protein involved in DNA repair, that can more accurately identify when pancreatic cancers would benefit from the addition of a PARP inhibitor (an emerging anticancer therapy) to standard chemotherapy than currently available assays. This is especially important for pancreatic cancer patients, for whom few effective treatments exist and, of those treatments, treatment-related toxicities are severe. Our approach will enable clinicians to identify pancreatic patients who are likely to response to PARP inhibitors, thus improving outcomes while reducing unnecessary toxicities.

Title: NEK9-MAP2K4: A Novel Signaling Axis Promoting Breast Cancer Growth and Chemotherapy Resistance

Principal investigators: Cynthia Ma, MD, PhD, an associate professor of medicine, and Jason Held, PhD, an assistant professor of medicine, both at Washington University School of Medicine, and both research members of Siteman Cancer Center

Goal: To understand the importance that two enzymes have in triple-negative breast cancer growth and their roles in causing resistance to different chemotherapy drugs used for treating triple-negative breast cancer

 

Description: Resistance to chemotherapy is a major cause of death in patients with breast cancer. There is a significant unmet clinical need to develop treatments that improve the effectiveness of chemotherapy by preventing the cancer cells’ ability to become resistant to the treatment. The researchers conducted a study to determine what molecules are causing resistance to cancer therapy and to learn how they work and interact with each other inside breast cancer cells. They identified a new process that allows breast cancer cells to become resistant to chemotherapy. Interrupting this process stops cells from dividing and makes them more sensitive to chemotherapy. The researchers found that high levels of enzymes called NEK9 or MAP2K4 are associated with a higher chance of cancer recurrence in patients with triple-negative breast cancer, which is a more aggressive type of breast cancer with a high risk of coming back after treatment. In this proposal, the researchers plan to learn more about how these enzymes work. They will test their importance and roles in making triple-negative breast cancer cells grow, and determine which type of chemotherapy could be effective in keeping this process from helping the cells grow. Lastly, they will examine whether high levels of enzyme activity is associated with resistance to chemotherapy in triple-negative breast cancer patients using samples obtained from patients who have all been treated with the same type of chemotherapy during their participation in an existing clinical trial. The long-term goal of this research is to develop a new treatment approach for triple-negative breast cancer which lowers the levels or activities of these enzymes to improve the effectiveness of chemotherapy, reduce the chance of recurrence and improve patient outcomes.

Title: Combined ketogenic diet and BCNU for recurrent pediatric brain tumors

Principal investigators: Joshua Rubin, MD, PhD, an associate professor of pediatrics, hematology and oncology, of neurology and of neuroscience; Joseph Ippolito, MD, PhD, an instructor in radiology; and Liu Lin Thio, MD, PhD, a professor of neurology, all at Washington University School of Medicine. Rubin and Ippolito also are research members of Siteman Cancer Center

Goal: To perform a first-in-kind clinical trial to determine whether a ketogenic diet can improve outcome when combined with chemotherapy for children with recurrent brain tumors 

Description: Survival for children with recurrent brain tumors is dismal, and there is a desperate need for new ways of thinking about treatment and better use of currently available therapies. This project seeks to do both by targeting brain tumor metabolism, a recognized but still immature approach to treatment. Cancerous growth requires adaptations in cellular metabolism. There is a large increase in sugar metabolism in particular, which is likely to constitute an Achilles heel for cancer cells. The researchers will perform a first-in-kind clinical trial to determine whether starving cancer cells of sugar with a ketogenic diet can improve outcome when combined with chemotherapy for children with recurrent brain tumors. This trial could establish St. Louis Children’s Hospital and Washington University School of Medicine as pioneers in the development of dietary approaches to cancer treatment.