Research related to breast, prostate, brain and pancreatic cancers are among the eight projects that will benefit from $1.75 million in new grants announced by Siteman Cancer Center. The grants, given through the Siteman Investment Program, are meant 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, the Fashion Footwear Association of New York; the National Cancer Institute; and the Barnard Trust.
The research projects are described below.
Title: A feasibility study to correlate cognitive changes of IDH-mutant and IDH-wildtype glioma patients after chemoradiotherapy with radiation dose to the resting state networks
Principal investigator: Jiayi Huang, MD, an associate professor of radiation oncology at Washington University School of Medicine in St. Louis and a research member of Siteman Cancer Center
Goal: To better understand how an advanced imaging technology called resting-state function magnetic resonance imaging (MRI) can be used to improve radiotherapy planning to reduce its negative impact on brain function for glioma patients
Project summary: Gliomas are malignant brain tumors that are typically treated with chemoradiotherapy. Patients may develop problems with their mental function after chemoradiotherapy, such as worse memory and attention. We know our brain is organized into different networks that control various mental functions, but we do not fully understand what networks are most sensitive to radiation injury to cause the observed decline of mental function. We have this advanced imaging technology called resting-state functional MRI (RS-fMRI) that can identify different brain networks. In the proposed study, we will perform RS-fMRI and detailed cognitive tests on glioma patients before and after their chemoradiotherapy. We will correlate changes of their test scores with radiation dose delivered to different networks on the RS-fMRI. This study will provide valuable background information regarding how we can use RS-fMRI to improve radiotherapy planning in the future to reduce its negative impact on brain function.
Title: A personalized neoantigen vaccine in patients with newly diagnosed glioblastoma using a novel DNA-based platform
Principal investigator: Tanner Johanns, MD, PhD, an assistant professor of medicine at Washington University School of Medicine in St. Louis and a research member of Siteman Cancer Center
Goal: To determine the safety and immunogenicity of a novel personalized vaccine approach in newly diagnosed glioblastoma
Project summary: Glioblastoma is the deadliest brain tumor in adults with few effective treatment options. This clinical trial aims to determine the safety and immunogenicity of a novel personalized vaccine approach in newly diagnosed glioblastoma. Neoantigens, derived from patient tumor-specific mutations, will be identified using a robust discovery pipeline, pVac-Seq, developed at Washington University. Neoantigens will be incorporated into a proprietary DNA vaccine platform in collaboration with Geneos Therapeutics that allows simultaneous expression of up to 50 neoantigens together with the potent immunostimulant adjuvant, IL-12. To date, previous neoantigen vaccine efforts have been limited to 20 candidates per patient and have failed to effectively prime CD8 T cells, which are critical for effective anti-tumor responses. If successful, the key advantages of this platform to prime robust CD8 T cells responses to a larger number of neoantigen candidates will serve as a new standard for neoantigen vaccinations in glioblastoma and other tumor types.
Title: Targeting CD44ICD as a mediator of pancreatic cancer growth and stemness
Principal investigator: Brian Dieckgraefe, MD, PhD, an associate professor of medicine at Washington University School of Medicine in St. Louis and a research member of Siteman Cancer Center
Goal: To develop ways to block a newly discovered pancreatic cancer signaling pathway that drives cancer growth and resistance to therapy
Project summary: Pancreatic cancer has the worst patient survival among all digestive tract cancers. Recent discoveries recognized that a population of human cells, called cancer stem cells are critical for tumor growth, its spread to other organs, therapy resistance, post-treatment recurrence and patient survival. We recently discovered a novel signaling pathway that is active in pancreatic cancer, as well as other cancers, that increases tumor growth and treatment resistance. A signaling molecule called Regenerating gene 4 protein (Reg4) binds to the cell surface CD44 receptor and directs clipping and release of a small protein peptide (the intracytoplasmic domain, CD44ICD) first into the cytoplasm and then into the nucleus of the cell. Inside the nucleus, CD44ICD turns on other pathways (gene programs) that appear to be responsible for rapid cancer growth. Like a conductor in an orchestra, this single peptide directs multiple different “instruments,” or pathways, that are used by tumors to grow rapidly and resist treatment. In this proposal, we are attempting to fully understand how CD44ICD works by identifying how it interacts with other critical cellular/nuclear proteins in pancreatic cancer. Results of this study will be used to design new drugs for pancreatic cancer treatment.
Title: Evaluation of diffusion basis spectrum imaging to non-invasively diagnose prostate cancer
Principal investigator: Eric Kim, MD, an assistant professor of surgery at Washington University School of Medicine in St. Louis and a research member of Siteman Cancer Center
Goal: To test the accuracy of a newly developed imaging tool in correctly predicting prostate cancer grade in patients noninvasively
Project summary: Prostate cancer is the most common cancer among men in the U.S. Unfortunately, the standard approach to diagnose prostate cancer requires a transrectal prostate biopsy, which is a very uncomfortable, invasive procedure that has medical risks such as sepsis. Prostate MRI has helped reduce unnecessary biopsies, but remains insufficiently accurate, for example, a false positive rate of more than 35 percent and a false negative rate of more than 15 percent. Our research team has developed a new tool for MRI analysis – diffusion basis spectrum imaging (DBSI). Using DBSI, we can noninvasively distinguish prostate cancer from cancer imitators. We can also use DBSI to accurately predict the prostate cancer grade in tumor samples. We plan to use DBSI on men who are undergoing prostate biopsy as per clinical care, to show that DBSI can noninvasively predict the biopsy results. If we are successful, we hope that DBSI can replace the majority of transrectal prostate biopsies.
Title: Predicting neoadjuvant treatment response of locally advanced rectal cancer
Principal investigator: Quing Zhu, PhD, a professor of biomedical engineering at Washington University School of Medicine in St. Louis and a research member of Siteman Cancer Center
Goal: To accurately assess and predict rectal cancer patients’ response to neoadjuvant radiation and chemotherapy and to select the best surgical strategy for each individual patient
Project summary: Rectal cancer is a prevalent disease that requires complex and coordinated care to achieve maximal survival while preserving a patient’s quality of life. Globally, 704,376 new cases of rectal cancer were reported in 2018, and more than 310,000 people died of this disease. Advances in the pre-operative treatment of these cancers have enabled 20 to 35 percent of locally advanced rectal cancer patients to achieve complete tumor death with radiation and chemotherapy alone. In these individuals, surgical resection has shown no benefit and poses a significant risk of major complications, prolonged recovery and reduced quality of life. However, the standard-of-care testing cannot adequately differentiate residual cancer from completely eradicated tumor sites in the treated rectum. In most instances, due to the uncertainty of post-treatment evaluation, physicians err on the side of over-treatment and operate on all eligible candidates. To assess rectal cancer patient treatment response before surgery, we have developed a new endoscopy imaging system using photoacoustic microscopy and ultrasound. We will optimize our prototype system, develop a novel machine-learning approach to accurately identify residual cancer from the treated tumor bed with scar tissue and conduct a pilot patient study.
Title: Leader cell development in cancer invasion
Principal investigators: Gregory Longmore, MD, a professor of medicine at Washington University School of Medicine in St. Louis, and Amit Pathak, PhD, an associate professor of mechanical engineering and materials science at Washington University in St. Louis. Both are research members of Siteman Cancer Center.
Goal: To determine the contribution of multiple environmental signals within breast tumors to metastasis
Project summary: The majority of breast cancer deaths result from metastatic disease. Accumulated evidence indicates that breast tumor cells invade as complex, heterogeneous clusters rather than single cells. To do so, they are led by cells called leader cells. Several hypotheses have been proposed to explain cancer leader cell development during collective migration. Yet how these leader cells develop, arrive and define the front edge, then lead directed collective migration, and whether this phenomenon is necessary and sufficient to effect directed collective migration, are largely unknown. We have developed novel microfluidic devices in which to study the collective migration. We propose to determine how leader cells develop and function, in response to multiple environmental signals, so as to direct collective migration.
Title: Examining cognitive decline in mice following a clinically mimetic brain irradiation protocol
Principal investigators: Stephanie Perkins, MD, an associate professor of radiation oncology; Adam Bauer, PhD, an assistant professor of radiology; Timothy Mitchell, PhD, an instructor of radiation oncology; and Francisco Reynoso, PhD, an assistant professor of radiation oncology, all of Washington University School of Medicine in St. Louis. Perkins and Bauer also are research members of Siteman Cancer Center.
Goal: To study the effects of radiation therapy on brain function and cognition to gain a comprehensive understanding of radiation-induced brain injury
Project summary: Radiation therapy is integral for achieving tumor control in many adult and pediatric brain tumors, but it can often lead to debilitating side effects on patients’ brain function and cognition. As survival outcomes improve, there is an increased need to improve quality of life for brain tumor survivors. The primary goal of the application is to study the effects of radiation therapy on the mouse brain to gain a comprehensive understanding of radiation-induced brain injury. Towards this goal, we will examine how whole brain radiation alters brain network communication and behavioral performance, and how these changes relate to cellular and molecular markers of brain injury. The ultimate goal is to develop and test therapeutic interventions in mice that could prevent or reverse radiation-induced injury in humans.
Title: Developing new therapies and delivery strategies for glioblastoma
Principle investigator: Milan Chheda, MD, an assistant professor of medicine at Washington University School of Medicine in St. Louis and a research member of Siteman Cancer Center
Goal: To develop treatments that will become the new standard of care for patients with glioblastoma
Project Summary: Glioblastoma (GBM) kills most adults within two years. Despite surgery, radiation, and temozolomide chemotherapy, most GBMs recur within six 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, nonoptimal dosing of chemotherapy and inadequate penetration of drugs across the blood–brain barrier (BBB) and throughout the tumor.
The Washington University GBM Team Science Group is composed of highly collaborative and interactive physician scientists with complementary expertise in immunotherapy, cell signaling, BBB biology and clinical trial design. Our pre-SPORE proposal will address each of these barriers to progress. Project 1 will perform pre-clinical testing, with toxicity studies, of Zika virus as a new therapy for GBM. Project 2 will characterize newly discovered cells in the brain that may modulate an anti-tumor defense and optimize therapies to enhance their function in patients. Project 3 develops our next clinical trial using laser ablation, pioneered at Washington University School of Medicine in St. Louis, in combination with the best therapy to kill GBM cells and initiate a powerful anti-tumor immune response. Project 4 builds on the fact that we are the only institution in the country performing circadian rhythm-based cancer treatment, and prepares us to launch a clinical trial based on optimal timing and combination therapy to substantially improve patient outcomes.