Siteman Investment Program awards $1.5 million in cancer research grants

Research focused on blood, brain, breast and colon cancers; improving awareness of the link between alcohol use and cancer risk; and clinical trials for high-risk prostate cancer and high-grade neuroendocrine neoplasms are among the projects that will benefit from $1.5 million in new grants announced by Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine.

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; Swim Across America – St. Louis; and the Alvin J. Siteman Cancer Research Fund.

The research projects are described below.

New Clinical Trial Mechanism

Title: Pilot Clinical Trial of Neoadjuvant SGLT2 Inhibition in High-Risk Localized Prostate Cancer

Principal Investigator: Melissa Reimers, MD
Co-Principal Investigators: Joseph Ippolito, MD, PhD, and Linda Peterson, MD

Goal: To assess the safety and tolerability of dapagliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor used to treat diabetes and heart failure, in patients with high-risk prostate cancer who will undergo surgical excision of the prostate. Researchers anticipate that four weeks of dapagliflozin therapy before surgery will not only be well-tolerated and safe but also will reduce the size of the tumor by targeting both systemic and tumor sugar regulation.

Summary: Dapagliflozin is a sodium-glucose cotransporter 2 (SGLT2) inhibitor used to treat diabetes and heart failure by changing how the body metabolizes sugar. Interestingly, multiple cancers, including prostate cancer, express SGLT2, indicating that dapagliflozin may have an additional advantage of preventing cancers from metabolizing sugar, thus improving outcomes. In this clinical trial, researchers will recruit men who have been diagnosed with high-risk localized prostate cancer and give them daily dapagliflozin four weeks before the surgical removal of their prostate. Physicians will closely monitor the patients for side effects and tolerability of dapagliflozin, and will use novel, state-of-the-art blood and imaging tests to measure tumor response before surgery. In summary, by targeting both the body’s and the tumor’s abilities to metabolize sugar, this therapy has the potential to lead to long-lasting beneficial outcomes for men with prostate cancer.

 

Established Clinical Trial Mechanism

Title: Cabozantinib in High Grade Neuroendocrine Neoplasms

Principal Investigator: Nikolaos Trikalinos, MD, MS

Co-Principal Investigator: Kian-Huat Lim, MD, PhD

Goal: The physician-researchers will evaluate the response rate of cabozantinib treatment in patients with high-grade neuroendocrine neoplasms that have progressed after first-line therapy. For the patients who respond, the physician-researchers will want to understand why it happened and who would benefit from the therapy in the future. For patients who don’t respond, the physician-researchers will want to understand how to combine cabozantinib with complementary pill treatments to bypass that resistance and augment its effect. The potential for infusion-free treatments and prolongation of meaningful life in this group of patients with rare, deadly tumors is very significant and can have a long-lasting impact for the patients and their loved ones.

Summary: One of the most difficult cancer problems to treat are high-grade neuroendocrine neoplasms (HG-NENs). At Washington University, researchers have developed an investigator-initiated clinical trial with an oral pill, cabozantinib, for patients with HG-NENs. Unexpectedly, the interim results have shown disease shrinkage in about 20% of the patients and stability in another 40%. Moreover, very recently, a trial showed that the same drug is active in neuroendocrine patients with slower-growing disease. To further the research, the physician-scientists will further study who benefits from cabozantinib and what makes cancer resistant to it.

The trial will continue to explore the effect of cabozantinib in patients with HG-NENs and document the final response rates and duration of effect. As a secondary endpoint, researchers will examine tissue samples from responding and nonresponding patients to help determine who would benefit from the treatment. The knowledge from the progressive patients can help researchers to understand how to potentially combine cabozantinib with complementary pill treatments to augment its effect. They hope to bring those results to a new clinical trial with a drug combination that might be even more successful.

This study is part of a large collaborative effort in the Washington University oncology group to improve outcomes in patients with gastrointestinal cancers, with particular interest in patients with pancreatic neuroendocrine neoplasms (about 40% of the high-grade disease population).

 

Pre-R01 Mechanism

Title: Posttranscriptional Regulation of the Telomerase RNA Component is a Major Determinant of Hematopoietic Failure in Telomerase Mutants

Principal Investigator: Luis Batista, PhD

Goal: To determine the potential of novel pathways regulating telomerase RNA stability to restore blood development and prevent cancer formation in patients with the cancer-prone bone marrow failure syndrome dyskeratosis congenita

Summary: Dyskeratosis congenita (DC) and aplastic anemia are cancer-prone bone marrow failure syndromes when patients come to clinical attention during infancy and early childhood. These patients have severely compromised development of blood cells, which results in a significantly increased chance of developing blood cancers. Patients diagnosed with DC have genetic alterations in genes that are important for the maintenance of telomeres, regions that represent the “ends” of each of chromosomes. Telomeres are essential to prevent chromosomes from being damaged or destroyed. Mutations found in DC patients cause very unstable telomeres, which lead to the accumulation of harmful lesions in DNA. This is followed by cellular failure and malignant transformation, a major step in cancer development. Currently, there is no treatment for children diagnosed with DC, as research on this severe syndrome has been hampered by a lack of adequate research models. To circumvent this issue the researchers engineered human stem cells harboring clinically relevant mutations that are found in patients, and developed technology to differentiate these cells in a controlled, quantitative fashion to become any particular blood cell type present in the circulatory system. This system allowed the researchers not only to reproduce the clinical defects of this disease with high precision but also to find alternatives to correct their molecular defect and restore blood development. For this project, the researchers will use this technology to study different strategies to restore telomere homeostasis in cells with mutations commonly found in patients. They aim to built from strong preliminary data and focus on pathways that can be modulated to prevent disease progression by restoring stem cell function, ameliorating blood development and preventing cancer formation. Successful completion will generate much-needed molecular knowledge to devise novel treatment strategies against this devastating disease.

 

Title: Brain Tumor Treatment as a Promoter of Tumor Recurrence

Principal Investigator: Milan G. Chheda, MD

Goal: Treatment for brain tumors negatively impacts the normal brain. Researchers seek to reverse this injury, which they believe will lengthen and improve the quality of patients’ lives.

Summary: The long-term goal of this project is to prevent brain tumor recurrence after treatment. Brain tumors are treated with radiation and chemotherapy. While these treatments kill tumor cells, they also cause premature aging of the brain, a process called senescence. These senescent cells, researchers believe, actually promote tumor recurrence because they make the brain environment more suitable for cancer cells to divide in and invade. Here, they seek to obtain preliminary data that supports these ideas. If correct, the researchers will contribute to the field by understanding how current treatments have paradoxical effects. They will develop ways to remove senescent cells from the brain and therefore extend and improve the lives of patients.

 

Title: Priming Antitumor T-cell Responses In Vivo with CAR Antigen Presenting Cells

Principal Investigator: Carl DeSelm, MD, PhD

Goal: Validate the efficacy of a new cancer immune therapy developed at Washington University that utilizes chimeric antigen receptor (CAR) technology in dendritic cells (DCs) to initiate new antitumor immunity, in mouse models and a translationally relevant human CAR DC product. This new curative intent treatment platform would be relevant to cancer patients across all histologies, including metastatic patients and those unresponsive to current immunotherapies.

Summary: Cancer immune therapy has improved the quality and quantity of many cancer patients’ lives, but the majority still do not achieve lasting responses. One challenge to current cancer immune therapies is that they often rely on the presence of previously activated immune cells, upon which “releasing the brakes” may allow them to continue to function and kill tumors. Those who lack this activated tumor-reactive population at baseline have poor outcomes. Activating only the cancer-specific immune cells while sparing the noncancer reactive immune cells (which can generate autoimmunity or toxicity) is not currently possible with any approved therapies. This therapy provides a mechanism of creating antitumor immunity by specifically activating cancer-targeting immune cells within the patient’s body, using advanced cell engineering techniques and antigen-presenting cells. This living drug harnesses the body’s sophisticated immune defenses to overcome the evasive nature of aggressive metastatic cancer.

 

Title: Mechanisms of Tumor Immune Evasion

Principal Investigator: Roberta Faccio, PhD

Goal: Reduce the risk of cancer recurrence and improve survival in patients with aggressive triple-negative breast cancer (TNBC) by targeting Dkk1, a molecule produced by both tumor and healthy cells in the bone or in proximity to cancer cells which supports tumor growth by reducing the ability of immune cells to kill tumor cells

Summary: Despite the majority of triple-negative breast cancer (TNBC) cases being diagnosed at an early stage and responding well to new standard-of-care therapies that consist of immune therapy in combination with chemotherapy, 30% of TNBC patients recur with metastatic disease within five years. Unfortunately, it is not known who will respond and who will relapse. Elevated levels of Dkk1 are detected in the blood and tumor biopsies of patients with aggressive disease and are associated with metastasis recurrence and poor survival. Dkk1 is a secreted molecule produced by both tumor and healthy cells in the bone or in proximity to cancerous cells. The researchers showed that Dkk1 supports tumor growth by reducing the ability of immune cells to effectively kill the tumor cells. Based on these observations, they hypothesized that Dkk1 could limit the efficiency of the standard of care in TNBC and be responsible for tumor recurrence. They now propose to correlate Dkk1 levels and the immune repertoire in tumor biopsies at baseline and at the time of surgery of TNBC patients receiving chemotherapy and immunotherapy in the neoadjuvant setting (before surgery). Results will determine whether patients with high expression of Dkk1 are less likely to respond to treatment. Ultimately, the goal is to design a clinical trial aimed at using DKN-01, a neutralizing antibody against Dkk1 that is available to the researchers, in TNBC patients in combination with standard-of-care chemotherapy and immunotherapy to efficiently reduce the risk of cancer recurrence and to improve patient survival.

 

Title: Circular RNA Encoded Peptides in Colon Cancer

Principal Investigator: Ryan Fields, MD, BS

Co-Principal Investigator: Christopher Maher, PhD

Goal: To deepen the understanding of how a new class of molecules known as circular RNAs (circRNAs) promote colorectal cancer (CRC) metastasis and chemotherapy resistance, with the ultimate goal of “drugging” these molecules to impede metastases and improve patient care

Summary: Colorectal cancer (CRC) is the most common gastrointestinal cancer in the US with approximately half of patients developing advanced disease. This represents an unmet clinical need to improve the current inadequate treatments. Currently, the limited understanding of how the original colon tumor spreads throughout the body (known as metastases) is a critical barrier to improved treatment. To address this, the researchers have been on the forefront of discovering a new class of molecules involved in colon cancer called circular RNAs, or circRNAs. In the current proposal, they are using cutting-edge techniques to study primary tumors and their metastases from the same patient to discover which specific circRNAs could be driving aggressive behavior. Further, their preliminary data revealed an overlooked mechanism in which a small section of the circRNA enables it to cause tumor spread/metastases and promote chemotherapy resistance. This proposal will integrate multiple technologies to provide the first roadmap of these critical functional regions within circRNAs. In the longer-term, they intend to use these valuable markers as indicators of metastatic progression and design novel methods to “drug” the critical regions of metastasis promoting circRNAs to improve patient care.

 

Title: Knowledge and Beliefs about Alcohol Consumption as a Risk Factor for Cancer

Principal Investigator: Amy McQueen, PhD

Goal: To inform future cancer risk decision-making and discussions in clinical practice by improving the public’s knowledge about the link between drinking alcohol and increased risk of developing cancer. The proposed formative research will provide rich mixed-methods data that will explain how participants process cancer risk information and will produce prototype messages to be tested in a future clinical trial.

Summary: Due to drinking alcohol, more than 75,000 people will develop cancer each year in the U.S. Even one to four drinks per day increases risk of head and neck, breast, and colorectal cancers. However, fewer than two drinks a day has been related to fewer kidney and thyroid cancers. Differences in how alcohol causes cancer, which cancers are affected, and the size of the risk for different people make cancer risk communication challenging. In the U.S., 66% of adults drank alcohol in the past month, and 70% are not aware of the cancer risk. To make trusted and effective public service messages or alcohol warning labels, research with diverse people is needed to understand which messages are best. In this study, researchers will invite 200 community members who drank alcohol at least three times in the past month to do a one-time survey. People who complete the survey and want to do future studies may be invited to do a one-time interview. The researchers will choose 24 people to do an individual interview and 24 to be interviewed in small groups. Having survey and interview data will provide a deeper understanding of how people think about their cancer risk and will let researchers compare this across different groups. Results will be used to design cancer risk messages that be tested in a larger study to increase knowledge and acceptance of the complex link between alcohol and cancer.