Siteman Investment Program awards $1.5 million in cancer research grants

Research on pancreatic cancer and on glioblastomas are among the seven projects that will benefit from $1.5 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; Swim Across America – St. Louis; Fashion Footwear Association of New York; National Cancer Institute; the Director’s Discovery Fund; and Barnard Trust.

The research projects are described below.

Title: Characterizing cancer cell intrinsic and immunologic phenotypes of estrogen receptor positive and HER2 negative breast cancer resistant to endocrine therapy and CDK4/6 inhibitor

Principal investigator: Cynthia Ma, MD, PhD

Goal: To develop biomarkers that predict a patient’s response to CDK4/6 inhibitors, the newest drugs available in the clinic for patients with stage IV estrogen receptor positive and HER2 negative (ER+/HER2-) disease, and to identify drug targets in resistant tumors, to design better treatments for breast cancer patients

Description: Estrogen receptor positive (ER+)/HER2 negative (HER2-) breast cancer (BC) represents more than 70% of breast cancer diagnosis and contributes to the majority of breast cancer deaths. Despite curative intent local and systemic treatments, up to 30% of patients who initially presented with early stage disease (localized to the breast and lymph nodes) will experience disease spread to distant organs (metastatic or stage IV) in the years to come. Cyclin-dependent-kinase (CDK) 4/6 inhibitors (CDK4/6i) are the newest drugs available in the clinic for patients with stage IV disease. However, up to 15% to 30% of patients do not benefit from these drugs. In addition, administrating a CDK4/6i in patients with early stage disease has not consistently shown to reduce recurrence. There is an unmet need for biomarkers that identify which patient will respond to CDK4/6i and to develop effective treatments for patients with resistant tumors.

In this proposal, we plan to perform in-depth molecular analysis of tumor biopsies collected from patients with locally advanced ER+/HER2- BC enrolled in the ongoing investigator initiated trial NeoPalAna (neoadjuvant palbociclib and anastrozole) that tests the efficacy of the CDK4/6i palbocilcib. The goal is to develop biomarkers that predict response to CDK4/6i and to identify drug targets in resistant tumors. We will perform tumor DNA and RNA sequencing as well as single cell proteomics using the state-of-the-art multi-plex immunofluorescent (MxIF) approach to interrogate the molecular characteristics of both tumor cells and immune cells in the tumor microenvironment. We expect to generate data needed to develop new diagnostic and treatment strategies for patients with ER+/HER2- BC.

Title: Reducing racial disparities in genetic testing for breast cancer in African American women

Principal investigator: Foluso Ademuyiwa, MD, MPH, MSCI

Goal: To test if using an African American facilitator who performs a rapid genetic risk assessment screening on African American women with breast cancer is feasible in the clinic setting, to improve the rates of provider recommendations for genetic counseling and testing and ultimately improve medical care for African American women with breast cancer

Description: Women carrying a BRCA mutation have a high risk of developing breast cancer. Genetic counseling and testing identifies high-risk individuals before breast cancer develops, allowing for personalized screening, preventive surgeries or medications to reduce risks. For those already diagnosed, identifying these genes leads to different treatment options. African Americans account for less than 5% of people who get testing for BRCA mutations and other breast cancer risk genes. Less than 60% of African Americans with breast cancer who ought to have testing for genetic mutations actually receive testing as part of their medical care. Studies show that medical providers have lower referral rates for African Americans, and are much more likely to refer Whites with breast cancer for genetic counseling and testing. Therefore, providers play a significant role in worsening racial disparities in the use of genetic services for African Americans with breast cancer. Our goal is to test if using an African American facilitator who performs a rapid genetic risk assessment screening on African American women with breast cancer is feasible in the clinic setting. We will also identify reasons why medical providers have lower rates of recommending genetic counseling and testing for African Americans, and investigate what information African American patients with breast cancer want to get from their medical providers about genetic counseling and testing. Our long-term plan is to improve the rates of provider recommendations for genetic counseling and testing and ultimately improve medical care for African Americans with breast cancer.

Title: MRI augmented X-ray imaging-guided adaptive radiotherapy for pancreatic cancer (MAX-guided ART)

Principal investigator: Taeho Kim, PhD

Goal: To take the lessons learned, tools and models available from MR-guided radiotherapy, an expensive tool that requires expertise not found in most clinics, and apply them to the more common X-ray guided radiotherapy to achieve effective treatment of pancreatic cancer in the standard clinic

Description: In 2019, pancreatic cancer was the ninth most common form of cancer in the United States but caused the second greatest number of cancer-related deaths. This disease is so deadly because it is often found at a late stage. Radiation therapy is effective at treating pancreatic cancer but difficult to deliver because the pancreas is surrounded by healthy organs very sensitive to radiation. Radiation therapy in combination with magnetic resonance imaging to guide the radiation (MRgRT) has proven to be one of the best tools to combat pancreatic cancer. However, MRgRT is very expensive and requires expertise not found in most clinics, but the more common X-ray guided radiotherapy (XgRT) cannot currently achieve the same success as MRgRT. The major goal of this project is to take the lessons learned, tools and models available from MRgRT and apply them to XgRT to achieve effective treatment of pancreatic cancer in the standard clinic. To do this we propose measuring tumor motion from high-speed MRI movies (cine MRI) and applying this information to tumor outlines on X-ray images used in XgRT. We will take advantage of a library of previously acquired pancreatic cancer images from clinical MRgRT and CT systems that is unique to our institution. Combining the benefits of MRgRT with conventional XgRT will enable a low cost but highly effective solution for pancreatic cancer treatment. This project can maximize the benefits of XgRT by taking advantage of the synergy brought by the combination of MRI for accurate tumor localization, respiratory motion management for comprehensive tumor motion control, and X-ray imaging-guided radiotherapy for rapid delivery.

Title: Identification of ubiquitin ligases and substrates specifically interacting with a new pancreatic cancer suppressor ABTB2

Principal investigators: Guangfu Li, PhD, and David DeNardo, PhD, in collaboration with the University of Missouri in Columbia

Goal: To further test the therapeutic efficacy of ABTB2-expressing virus in clinically relevant KPC mice and patient-derived xenograft mice toward the ultimate clinical trial in patients with pancreatic cancer and identify ABTB2-specific interacting partner protein for developing novel targeted therapies for pancreatic cancer

Description: Pancreatic cancer (PaC) is one of the most lethal human malignancies and the fourth leading cause of cancer-related death without effective treatment. Conventional therapeutic options, including surgery, chemotherapy and radiation therapy provide very limited benefit to human patients. The development of a new, efficient therapeutic approach for PaC is urgently required. We have identified such a new target for PaC. We have found that a gene called ABTB2 has a strong effect in suppressing PaC growth. We have constructed a therapeutic virus to infect PaC cells and manipulate ABTB2 expression, and found that this can significantly induce suppression of PaC growth without detectable adverse effects. We propose to further test the therapeutic efficacy of ABTB2-containing virus in two additional models of PaC and identify the pathways that mediate ABTB2’s function. The generated data will help us select patients for an ABTB2-targeted therapy and advance our agent towards clinical testing.

Title: Predicting head and neck cancer outcomes using partial epithelial-to-mesenchymal transition biomarker

Principal investigator: Angela Mazul, PhD, MPH

Goal: To develop a reliable genomic test to guide treatment decision-making in oral cavity cancer patients across diverse socioeconomic and demographic groups

Description: The anatomy of the oral cavity is complex, with features necessary to speech and eating. Thus, treating oral cavity cancer must be carefully balanced between cancer outcomes – such as recurrence and survivorship – and quality of life – such as speech, swallow and taste. At the same time, there are severe racial and socioeconomic disparities in cancer outcomes. Black oral cavity patients have worse survival and receive lower quality treatment than White patients, even when considering socioeconomic status. Thus, there is a critical need to develop a reliable genomic test to guide treatment decision-making in oral cavity cancer patients across diverse socioeconomic and demographic groups.

We developed a biomarker using RNA genetic material from oral cavity tumors. This biomarker predicts which cancers are more aggressive, as well as poor cancer outcomes. Early data also suggest the biomarker may also capture racial disparities and differences. Our study aims to further develop our innovative biomarker in a diverse cohort constructed from oral cavity patients treated at Barnes-Jewish Hospital and Washington University School of Medicine in St. Louis. Additionally, we will study how this biomarker interacts with race and socioeconomic status.

This line of research will help us understand the relationship between our oral cavity biomarker, race, socioeconomic status and cancer outcomes. These results will advance precision medicine for oral cavity cancer by challenging current approaches by integrating genomics with socioeconomic status.

Title: HPV genomic structural subtypes in oropharyngeal squamous cell carcinoma

Principal investigators: Jose Zevallos, MD, MPH, and Jin Zhang, PhD

Goal: To understand both how and why “high-risk HPV genomic structures” may be a useful biomarker of high-risk disease for HPV-associated oropharyngeal cancer and ultimately better identify the high versus low risk patients at the time of diagnosis

Description: Human papillomavirus (HPV) is a common viral infection which can cause a number of cancers including oropharyngeal squamous cell carcinoma (OPSCC). The rate of HPV-associated OPSCC is rising in the United States and abroad. Using next-generation sequencing technology, our laboratory has recently identified specific features of HPV within tumor cells that are associated with significantly lower overall survival. We call these “high-risk HPV genomic structures” (HRGS). This is important because 4 of 5 patients with HPV-associated OPSCC survive their disease, but it is difficult to predict in advance of treatment who is likely to survive or fail treatment. We believe our findings could represent an important biomarker of high-risk disease, which would allow us to better identify the high versus low risk patients at the time of diagnosis. The work proposed in this grant will accomplish two tasks. First, we will advance HRGS toward use as a cancer biomarker by creating and testing a computer program which will detect HRGS from highly complex datasets. We will determine how much better we can identify high versus low risk disease compared to our existing methods, which mainly use gross measures of how advanced the disease is at time of diagnosis. We will also perform experiments which evaluate a potential mechanism which would explain why patients with HRGS have worse outcomes. The results of this work will help us better understand both how and why HRGS may be a useful biomarker of high-risk disease for HPV-associated oropharyngeal cancer.

Title: Washington University Glioblastoma Team Science: An integrated and collaborative approach to develop new therapies for glioblastoma

Principal investigators: Milan Chheda, MD (principal investigator); Michael Diamond, MD, PhD; Tanner Johanns, MD, PhD; Gavin Dunn, MD, PhD; Kenneth Murphy, MD, PhD; Allegra Petti, PhD; Hong Chen, PhD; Albert Kim, MD, PhD; Robyn Klein, MD, PhD; Jian Campian, MD, PhD; Erik Herzog, PhD; Joshua Rubin, MD, PhD; and Jingqin (Rosy) Luo, PhD 

Goal: To develop new ways to treat patients with glioblastoma based on discoveries made at Washington University in St. Louis

Description: The long-term goal of this proposal is to develop treatments that will become the new standard of care for patients with glioblastoma (GBM). The Washington University GBM Team Science group represents seven departments at Washington University, including both the Medical and Arts and Sciences campuses and clinicians who treat adults and children. These physicians and scientists have complementary expertise in cancer therapeutics, immunology, clinical trial design, circadian biology, pathology and engineering and all are singularly focused on developing innovative ways to treat and cure GBM.

GBM kills most adults within two years. Despite surgery, radiation and temozolomide chemotherapy, most GBMs recur within 6 months. There is no standard of care for recurrent GBM. Recurrence and treatment resistance is driven, in part, by the existence of cancer stem cells, poor anti-tumor immunological response, non-optimal dosing of chemotherapy and inadequate penetration of drugs across the blood-brain barrier and throughout the tumor.

This pre-SPORE proposal will address each of these barriers. In project 1, the team will develop zika virus as a new therapy for GBM. In project 2, they are developing ways to engage an underappreciated immune cell to launch a better anti-tumor defense. In project 3, they will develop new understanding on how laser and ultrasound treatment of tumors increases delivery of chemotherapy and may be combined with other treatments. In project 4, they pursue exciting findings that circadian rhythms may make a major difference in how patients respond to treatment.