Siteman Investment Program awards $1.6 million in cancer research grants

Research on melanoma and breast and colon cancer are among the seven projects that will benefit from $1.6 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.

Direct pharmacological targeting of Gq/11 in uveal melanoma

Principal investigator: Kendall Blumer, PhD, a professor of cell biology and physiology at the School of Medicine and a research member of Siteman Cancer Center

Amount: $400,000 over two years 

Goal: To complete preliminary tests of the first pharmacological approach to treat uveal melanoma (UM) in tumor samples and animals and ultimately determine if these compounds could lead towards a first-in-class, targeted treatment for UM patients

Description: Uveal melanoma (UM) is the most common tumor within the eye in adults. Nearly half of UM patients develop metastatic disease with mean overall survival of 6-12 months. Rates of metastatic disease and mortality are unchanged by treating primary tumors, and proven therapies for metastatic UM do not exist. A major roadblock is the absence of therapies that inhibit the tumor cell-driving proteins in UM. This project describes the first pharmacological approach toward targeted therapy in UM. It uses compounds that specifically inhibit the tumor cell-driving proteins in UM. It will determine whether these compounds provide leads toward first-in-class, targeted therapeutics by analyzing their effects on patient-derived UM tumor samples and in mouse models of UM. Studies of these inhibitors could lead eventually to the first true therapeutic breakthrough in metastatic UM.

Targeting HER2 activating mutations in metastatic breast cancer

Principal investigator: Ron Bose, PhD, MD, an associate professor of medicine at the School of Medicine and a research member of Siteman Cancer Center

Amount: $200,000 over two years

Goal: To enable the next line of clinical trials for HER2-activating mutations in metastatic breast cancer patients by studying neratinib-based drug combinations in animal models 

Description: Metastatic breast cancer causes 40,000 deaths per year in the U.S. We identified HER2-activating mutations (HER2mut) as an uncommon but highly treatable mutation in metastatic breast cancer, and we have successfully performed a multi-institutional, phase II clinical trial treating HER2mut metastatic breast cancer patients with the HER2 tyrosine kinase inhibitor, neratinib. Several key observations were made from this clinical trial, including the fact that more than 90 percent of the HER2mut metastatic breast cancer patients had estrogen receptor-positive breast cancer. We will study neratinib-based drug combinations using two types of mouse models of HER2mut breast cancer. This research will enable the next line of clinical trials for HER2mut metastatic breast cancer patients.

The role of onco-lncRNA-230 as an epigenetic regulator of colon cancer metastasis

Principal investigator: Christopher Maher, PhD, an assistant professor of medicine at the School of Medicine, an assistant director at The McDonnell Genome Institute and a research member of Siteman Cancer Center

Amount: $200,000 over two years 

Goal: To develop new treatments for colorectal cancer by studying a recently discovered molecule that plays a central role in enabling a primary tumor to develop in distant organs

Description: Colorectal cancer is the most common gastrointestinal cancer in the U.S., with about half of patients developing advanced disease. Of them, more than 80 percent will succumb within 5 years. This represents an unmet clinical need to improve the current inadequate treatments. Currently, our limited understanding of the ways in which the original colon tumor spreads throughout the body, or metastases, is a critical barrier for improved treatment. To address this, we studied primary tumors and their metastases from the same patient to discover a new class of molecules involved in metastasis called lncRNAs. Based on our preliminary data, we will study a promising lncRNA acting as a “master regulator” by interacting with specific proteins to alter their normal function and cause the tumor to spread. Later, we intend to evaluate methods to inhibit, or “drug,” this lncRNA, ultimately leading to the development of novel therapeutics for improving outcomes in this deadly disease.

Functional regulation of DNA damage response by the ubiquitin-selective protein segregase VCP

Principal investigator: Jieya Shao, PhD, an assistant professor of medicine at the School of Medicine and a research member of Siteman Cancer Center

Amount: $200,000 over two years

Goal: Understand chemotherapy resistance in breast cancer patients to develop novel and reliable ways to predict treatment response and sensitize resistant patients to chemotherapy

Description: Chemotherapeutic resistance is a huge clinical problem facing both oncologists and cancer patients. As such, we urgently need to understand the resistance mechanisms and develop predictive biomarkers for both treatment response and chemo-sensitizing methods. One way cancer cells resist chemotherapy is by increasing their ability to repair treatment-induced DNA damage. This depends on the coordinated actions of DNA repair proteins and their dynamic, timely assembly and disassembly at the damage sites. With this grant, we will investigate VCP, a protein known to facilitate the timely removal of repair factors from DNA during damage response. Specifically, we will focus on a phosphorylation event of VCP that is induced by DNA damage and whose level inversely correlates with breast cancer outcome. Based on preliminary data, we hypothesize that VCP phosphorylation plays an important role in DNA damage response and may greatly influence cancer cell response to genotoxic chemotherapies. The experiments are designed to test this hypothesis. If successful, they will rationalize future investigation of the clinical value of phospho-VCP as a predictor of cancer chemotherapy response and a novel target of chemo-sensitization. 

Optimizing fall-risk prediction in older adults with cancer

Principal investigator: Tanya Wildes, MD, an assistant professor of medicine at the School of Medicine and a research member of Siteman Cancer Center 

Amount: $200,000 over two years

Goal: To better understand the risk factors associated with falls in older adults with cancer and, ultimately, to create a tailored fall-prevention intervention that can be tested in a clinical trial

Description: Each year, one in three older adults falls. Older adults with cancer are at even greater risk; as many as half fall every six months. This may be due to medications that cause unsteadiness, weakness, treatment side effects, and nerve damage from chemotherapy, but exactly which risk-factors are most important is not known. It is also unknown how risk changes over time in older adults receiving cancer treatment. In this study, we will follow 200 older adults receiving cancer therapy for 6 months to determine risk factors for falls. The ability to identify people at greater risk for falls, coupled with another current project adapting a fall-prevention intervention for older adults with cancer, will provide the necessary elements to conduct a clinical trial of a fall-prevention intervention, tailored to the needs of older adults with cancer, and targeted to those at greater risk.

DNA damage mediated checkpoints in early B cell development

Principal investigator: Jeffrey Bednarski, MD, PhD, an assistant professor of pediatrics at the School of Medicine and a research member of Siteman Cancer Center

Amount: $200,000 over two years

Goal: To advance our understanding of the development of pediatric leukemia and identify new treatments by studying a newly identified cellular signaling pathway that can play a role in leukemic cell growth and survival.

Description: Pre-B acute lymphoblastic leukemia (ALL) is the most common cancer in children. However, remarkably little is known about the basis of the initiation and maintenance of this leukemia. During normal development, immune cells rely on signaling from surface receptors to drive cell growth and generate a diverse immune response. Pre-B leukemic blasts have errors in the signaling from these receptors that supports their uncontrolled growth and survival. Thus, these signals must be carefully balanced to support normal immune cell growth but prevent transformation into leukemia. We have identified a novel mechanism that controls surface receptor signaling in immune cells. Our goals are to understand how this signaling circuit is coordinated to direct early B cell development and how corruption of this pathway leads to leukemia. We expect that these studies will provide important insights into the development of leukemia and will identify novel therapeutic targets in pediatric ALL.

Mechanism and inhibition of PALB2 and BRCA2 proteins

Principal investigator: Sergey Korolev, PhD, an associate professor of biochemistry and molecular biology at Saint Louis University School of Medicine and a research member of Siteman Cancer Center

Amount: $200,000 over two years 

Goal: To better understand how two tumor suppressor proteins are involved in cancer and the development of resistance to drugs used in cancer treatment, and to find inhibitors of these proteins that could be used to improve anticancer therapy or develop alternative treatments in the future

Description: We propose to study how mutations in the BRCA2 and PALB2 tumor suppressor proteins lead to cancer and the development of drug resistance during cancer treatment. We will study how these proteins normally work in the cell to repair broken chromosomes, and evaluate the disease-causing potential of mutations to one or both of these proteins. In addition, we will isolate BRCA2 and PALB2 to discover inhibitors of these proteins, which can be used to improve the effectiveness of anticancer therapies and also could be used to discover alternative treatments for the diseases caused by these mutations.