Research on colon cancer, breast cancer and acute myeloid leukemia are among the seven 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; Fashion Footwear Association of New York; National Cancer Institute; and Barnard Trust.
The research projects are described below.
Title: Pilot Implementation and Feasibility Assessment: Multilevel Intervention to Reduce Rural Colon Cancer Disparities
Goal: To develop a multi-level intervention to improve colon cancer screening and follow-up in primary care clinics in rural Southern Illinois
Summary: Rural areas in the Midwest face higher rates of colon cancer mortality. Screening can help reduce the burden, but screening rates are relatively low in rural areas. Further, many people who get screened do not receive appropriate diagnostic follow-up, especially if they were screened with fecal testing. Better and more consistent implementation of strategies that we know can be effective can help underserved communities increase screening and improve follow-up of abnormal cancer screening tests. Interventions at multiple levels are critical to success, as intervening on patients or primary care providers alone is unlikely to have substantial impact. We have partnered with Southern Illinois Healthcare to develop a multi-level intervention using evidence-based strategies to improve screening and follow-up in primary care clinics in rural Southern Illinois.
Title: Retinoid Therapy in Acute Myeloid Leukemia
Principal investigator: John Welch, MD, PhD, an associate professor of medicine at Washington University School of Medicine and a research member of Siteman Cancer Center
Goal: To determine if two existing acute myeloid leukemia (AML) drugs are more effective when administered in combination with each other using mouse and human models
Summary: This project focuses on completing the required pre-clinical studies needed to translate a benchtop observation into a clinical trial in acute myeloid leukemia (AML). We found that two old drugs, all-trans retinoic acid and bexarotene, exhibit strong synergy when added together in a mouse model of AML, whereas they have very modest activity by themselves. Both drugs are FDA approved, are orally available and have well-characterized and tolerable side effects. In this proposal, we will determine whether this combination is highly active in other mouse and human models of AML, or if these drugs are only active in this one mouse model of AML (MLL-AF9). In addition, we will work with medicinal chemists at Washington University to make multiple subtle changes in the chemical structure of bexarotene, and determine whether any of these changes augment the synergistic interaction and could improve on bexarotene as anti-leukemic agents. These results will form the justification for future clinical trials in AML.
Title: Oral Microbiome, Virome and Barrett’s Esophagus
Principal investigator: Yin Cao, ScD, an assistant professor of surgery at Washington University School of Medicine
Goal: To better understand the relationship between bacteria in one’s oral cavity and a person’s future risk of developing Barrett’s esophagus and esophageal adenocarcinoma
Summary: In the U.S., esophageal adenocarcinoma (EAC) has had a nearly seven-fold increase in incidence over the last four decades. However, EAC is highly lethal compared to other cancers, in that 80 percent of EAC patients succumb to the disease within 5 years. The prevention and early detection of EAC and Barrett’s esophagus (BE), the established premalignant lesion of EAC, is a high clinical priority and research challenge. Bacteria and virus may be important to this disease process but studies are limited. Project 1 will, for the first time, examine bacteria in the oral cavity and how that relates to future risk of BE in two large studies that have followed an initially healthy population for more than 30 years. Project 2 will look into whether viruses in the saliva samples collected from the above studies could be detected, as well as from esophageal samples collected from BE patients in a large hospital based cohort. The two projects will provide novel knowledge on BE/EAC development.
Title: Radio-sensitization by Free Fatty Acid Supplementation in Cervical Cancer
Principal investigator: Julie Schwarz, MD, PhD, an associate professor of radiation oncology at Washington University School of Medicine and a research member of Siteman Cancer Center
Goal: To explore why obese patients treated with radiation therapy for cervical cancer have better response rates than patients who are not obese, with the ultimate goal of identifying a dietary supplement or drug that can be given to patients to promote better treatment responses
Summary: Many patients struggle with obesity, and studies have shown that obese cancer patients treated with surgery and chemotherapy have poor outcomes. Surprisingly, we have found that obese patients treated with radiation therapy for cervical cancer are cured more often than patients who are not obese. Obese patients have increased body fat and circulating levels of fats. In the laboratory, we have shown that free fatty acids enhance the effects of radiation. After radiation treatment, cancer cells actively take up fatty acids, and this results in changes in cell signaling that promote tumor cell death. In this grant, we will perform additional experiments in cells and animal models to understand how free fatty acids and obesity are promoting the response to radiation therapy. Our ultimate goal is to identify a dietary supplement or drug that we can give to patients that will promote treatment sensitivity.
Title: Intravenous Lidocaine for Preventing Oxaliplatin-induced Peripheral Neuropathy (OIPN)
Principal investigator: Simon Haroutounian, PhD, an assistant professor of anesthesiology at Washington University School of Medicine
Goal: To determine if lidocaine can reduce the occurrence and severity of oxaliplatin-induced peripheral neuropathy, a painful common side effect of chemotherapy
Summary: Colorectal cancer is the second leading cause of cancer-related death in the U.S. Oxaliplatin is a key chemotherapy agent demonstrating improved survival in colorectal cancer, but causes injury to sensory nerves in 72 percent of patients receiving treatment. This nerve damage, called peripheral neuropathy (PN), can cause substantial pain, numbness and sensory changes such as extreme sensitivity to cold. PN leads to dose reduction or early discontinuation of oxaliplatin in 50 to 70 percent of patients, reducing patient survival by 5 to 14 months. In approximately 20 percent of patients, oxaliplatin-induced PN persists for months or years after chemotherapy. The study aims to determine whether intravenous lidocaine can reduce the incidence and the severity of oxaliplatin-induced PN. In a prospective, randomized study, patients with colorectal cancer will receive lidocaine or placebo with their standard-of-care oxaliplatin-based chemotherapy. The key outcomes, compared between the groups, include: 1) symptoms and signs of peripheral neuropathy, 2) cumulative dose of oxaliplatin and 3) adverse effects.
Title: Genomic Classification and Targeted Immunotherapy of Disseminated Tumor Cells in Breast Cancer Patients
Principal investigators: Siteman Cancer Center research members Rebecca Aft, MD, PhD, a professor of surgery; Mark Watson, MD, PhD, an associate professor of pathology and immunology; and Leonel Hernandez-Aya, MD, an assistant professor of medicine, all of Washington University School of Medicine
Goal: To better understand how to develop new therapies to eliminate disseminated tumor cells in triple negative breast cancer patients, to prevent the cancer from metastasizing
Summary: Treatment of triple negative breast cancer is challenging since there are a limited number of new and highly effective therapies. This subset of breast cancer patients has a high risk of disease recurrence and death when traditional chemotherapy is used. Small deposits of disseminated tumor cells released from the breast tumor, detected in the bone marrow of some triple negative breast cancer patients before and after chemotherapy treatment, identify patients with a particularly high risk of developing metastatic disease. It is thought that metastatic disease develops in these patients because these tumor cells themselves are resistant to therapy and because other environmental factors selectively support their growth and survival. We have developed a very sensitive 8-gene molecular biomarker panel that can identify triple negative breast cancer patients who have disseminated tumor cells in their bone marrow and who have a high risk of cancer recurrence. In this project, we will isolate and further characterize the genetics of individual disseminated tumor cells from triple negative breast cancer patients, to better understand how to develop new therapies to eliminate them and prevent metastatic disease. We will also examine whether and how a patient’s own immune cells contribute to the survival of disseminated tumor cells in the bone marrow. Importantly, we will conduct a pilot clinical trial to determine whether altering the function of immune cells in a patient’s bone marrow can help eliminate these tumor cells and prevent future metastatic tumor recurrence. Overall, these studies are geared to discover novel therapeutic strategies to eliminate disseminated tumor cells and potentially improve long-term survival in patients with triple negative breast cancer.
Title: Advancing Therapies for Incurable Lymphomas via Translational Team Science
Principal investigator: Siteman Cancer Center research members Todd Fehniger, MD, PhD, an associate professor of medicine and Brad Kahl, MD, a professor of medicine, both of Washington University School of Medicine
Goal: To develop and evaluate new treatments for patients with incurable lymphomas
Summary: The long-term goals are to advance novel basic findings in lymphoma into the clinic via development of a comprehensive and innovate translational research program. Specific projects seek to:
- Investigate new immunotherapy treatment combinations in early phase clinical trials, to boost indolent lymphoma patients’ natural killer, or NK, cells, and to further enhance NK cell targeting of lymphoma cells via modification with specialized chimeric antigen receptors (CAR);
- Understand how changes in lymphoma cells’ DNA result in follicular lymphoma, and translate these genetic findings into new ways to help with lymphoma patient prognosis and develop new personalized lymphoma-specific vaccine therapies;
- Develop next-generation “universal” CAR T cells to reduce barriers to lymphoma patients receiving CAR-modified T cellular therapy, and explore new strategies to enhance CAR-T cell persistence;
- Determine how changes in the structure of DNA (epigenetic) impact response to treatment and progression in very hard-to-treat T cell lymphomas; and
- Understand the role of key activated receptor pathways (growth signals) for aggressive T-cell lymphoma/leukemia, and advance a new combination clinical trial of chemotherapy combined with a growth pathway inhibitor.
These projects will include or lead to new clinical trials for lymphoma patients, with the ultimate goal of curing lymphoma.