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Siteman Investment Program awards $1.3 million in cancer research grants

Washington University School of Medicine

Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine is pleased to announce funding for six new projects, including research focused on survivorship as well as specific cancers such as breast, head and neck, lung, prostate, neuroblastoma, and osteosarcoma. These projects will benefit from $1.3 million in new grants through the 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.

New Clinical Trial Mechanism

Project Title: Early Phase I Window of Opportunity Trial of Pyrimethamine as an Inhibitor of NRF2 in HPV-negative Head and Neck Squamous Cell Carcinoma

Ben MajorPrincipal Investigator: Ben Major, PhD

Goal: Test the pyrimenthamine drug as an inhibitor of the NRF2 protein in head and neck squamous cell carcinoma, which if proven true could result in the ability to sensitize NRF2-active cancers to standard of care chemotherapy, radiation therapy, and immune inhibition therapy.

Project Summary: Patients suffering advanced head and neck squamous cell carcinoma (HNSCC) face poor prognoses and limited treatment options. Massive DNA sequencing efforts have revealed genes, that when mutated, contribute to HNSCC progression and resistance to chemotherapy and radiation therapy. Principle among these is the NRF2 gene, which for decades has been known to protect normal cells from stress and environmental toxins like air pollution and sun exposure. The evolution of a normal cell to a cancer cell is exceedingly stressful to cellular life, and as such, mutation and activation of NRF2 provides the growing cancer with critical survival capabilities. Moreover, HNSCC cancers with NRF2 mutations and activation have been shown to be resistant to front line chemotherapy, radiation therapy and immune-directed therapy.

We recently discovered that the drug Pyrimethamine has an inhibitory effect on NRF2 activity in cell culture models and in mouse models. Mechanistically, we found that Pyrimethamine inhibits the dihydrofolate reductase (DHFR) enzyme, and that this results in inhibition of NRF2. Pyrimethamine is an FDA approved drug that has been used for decades for treatment of protozoan infections and malaria.  A growing body of research shows that it has potential antitumor activity, however it has not been previously studied in HNSCC or specifically in the context of NRF2-active tumors.

In this study of HNSCC patients with advanced disease, we will determine if Pyrimethamine treatment for two weeks results in loss of activity of DHFR and NRF2. If proven true, these data will support a near-future Phase 2 clinical study wherein we test whether Pyrimethamine sensitizes NRF2-active cancers to standard of care chemotherapy, radiation therapy, and immune inhibition therapy.

Pre-R01 Mechanism

Project Title: Pif1 Helicase as a Target for Inhibition in ALT+ Cancers

Roberto Galletto

Principal Investigator: Roberto Galletto, PhD

Goal: Define the role of Pif1 in telomere maintenance in cancer cells and to identify small molecule inhibitors to test the functional outcome of Pif1 inhibition.

Project Summary: One hallmark of cancer cells is their ability to maintain the ends of their chromosomes, in a special DNA structure called telomeres. This gives cancer cells the ability to replicate indefinitely. In general, telomere maintenance in cancer cells occurs via reactivation of a protein called telomerase, a specialized enzyme that extends the DNA length of telomeres. However, in about 10-15 percent of tumors, telomeres are maintained by a telomerase-independent pathway, termed Alternative Lengthening of Telomeres (ALT).

As neither normal cells nor majority of tumors rely on ALT, specific inhibition of this pathway provides an attractive target for therapeutic intervention specifically tailored to ALT+ cancers. However, the mechanisms of ALT in human tumors and suitable targets for small molecule inhibition have remained elusive. To this end, we identify human Pif1, an enzyme that unwinds the DNA double helix and facilitates DNA replication at hard-to-replicate sites, as a candidate to be targeted for inhibition in ALT.

Project Title: Investigating GSTP1 Structure and Signaling in Breast Cancer

Jason Held

Principal Investigator: Jason Held, PhD 

Goal: Address critical knowledge gaps in our functional and mechanistic understanding of how silencing the enzyme GSTP1 re-wires cysteine oxidation of the proteome in breast cancer, hopefully providing new ways to inhibit breast cancer growth and transformation.

Project Summary: Glutathione S-transferase Pi 1 (GSTP1) is an enzyme that we find is uniquely and dramatically downregulated in luminal and some Her2-positive breast cancers, as well as liver and prostate cancers. This proposal will investigate how GSTP1 acts as a tumor suppressor via regulation of cysteine oxidation in proteins. This is a novel function for GTP1, so we will characterize its structure and role in cancer signaling.

Project Title: Understanding the Role of the IncRNA, RAMS11, in Lung Cancer

Christopher MaherPrincipal Investigator: Christopher Maher, PhD

Goal: Understand how our recently discovered lncRNA, RAMS11, interacts with a pioneering transcription factor to promote tumor growth and metastasis in non-small cell lung cancer patients.

Project Summary: Lung cancer is the most common malignancy and has the highest mortality worldwide, with approximately 80-85 percent of all lung cancer patients categorized as being non-small cell lung cancer (NSCLC). Despite improvements in diagnosis and treatment options, currently only five percent of NSCLC patients with aggressive disease survive five years or longer. This represents an unmet clinical need to improve the current treatments.

To address this, NSCLC research has primarily focused on understanding which genes that produce proteins, also known as protein-coding genes, have altered activity in tumor cells compared to normal cells. However, our lab recently discovered a novel class of genes that eluded researchers because, contrary to central dogma, they enable a cell to function without generating a protein (we refer to as long non-coding RNA [lncRNA] genes). Building on this discovery, our lab is focusing on how these understudied lncRNA genes enable a lung tumor to develop and eventually spread throughout the body (also known as metastases).

More specifically, we recently discovered a lncRNA that becomes more active in lung cancer patients that have more aggressive disease. The current proposal will study how this lncRNA acts as a “master regulator” by interacting with specific proteins to alter their normal function and cause the original tumor to grow and spread. In the longer-term we intend to “drug” this lncRNA, ultimately leading to the development of novel therapeutics for improving outcomes in this deadly disease.

Project Title: Prehabilitation to Revolutionize Oncology: Telehealth Exercise for Cognitive Triumphs (PROTECT)

Elizabeth SalernoPrincipal Investigator: Elizabeth Salerno, PhD, MPH 

Goal: Determine the feasibility and preliminary efficacy of a physical therapist-delivered prehabilitation physical activity intervention to prevent cognitive decline in breast cancer patients undergoing chemotherapy, hopefully leading to a significant paradigm shift in the way we implement standard of care rehabilitation during cancer survivorship.

Project Summary: Despite chemotherapy’s effectiveness at treating breast cancer, many patients experience severe declines in cognitive function during treatment that can persist for years. Our team’s previous research suggests that regular physical activity may help, but randomized controlled trials are necessary to confirm these findings. Our research also suggests that physical activity should begin as soon as possible after a cancer diagnosis, but most targeted physical activity interventions are designed to begin after chemotherapy completion, once cognition has already declined.

Interventions delivered before or during treatment (e.g., prehabilitation) may be better suited to prevent treatment-related impairments and improve prognosis; however, these trials are difficult in practice. Oncologists have limited (if any) time to systematically advise patients on physical activity behavior, and patients are overwhelmed by a new cancer diagnosis and hesitant to begin activity on their own without proper support. Ideal models of cancer care should be pragmatic, which includes referral to physical activity programs through existing healthcare pathways to support enrollment, adherence, and long-term behavioral maintenance.

To address these gaps, we propose to conduct a pilot randomized controlled trial exploring both the preliminary efficacy and feasibility of a remote, physical therapist-delivered prehabilitation physical activity intervention to prevent cognitive decline in breast cancer patients undergoing chemotherapy, compared with a wait-list control condition. Findings from this study will provide critical preliminary data for scaling our intervention to confirm the role of physical activity on cognitive function and implement pragmatic approaches to prehabilitation during treatment for breast cancer.

Project Title: Next Generation Theranostic 89Zr/227Th-conjugated PSMA Inhibitor for Precision Molecular Imaging and Radiotherapy of Metastatic of Prostate Cancer

Hanwen ZhangPrincipal Investigator: Hanwen Zhang, PhD

Goal: Advance a next generation theranostic pair with a novel compound, 89Zr/227Th-Lumi-PSMAUrea, for targeting imaging and alpha particle therapy of metastatic prostate cancer.

Project Summary: Prostate cancer (PCa) is the most common non-cutaneous malignancy diagnosed in men and is their second leading cause of cancer death. Over 90 percent of these cancer cells overexpress a cell-surface protein, prostate specific membrane antigen (PSMA). Radiopharmaceuticals that target PSMA can be used to sensitively detect and characterize PCa, as well as direct cancer-specific radiation to sites throughout the body. The FDA has recently approved several PSMA-agents for imaging and targeted therapy. However, the overall survival extension of Lutetium-177 labeled therapeutics is only four months, due to the low absorbed dose at sites of disease from this low energy beta particle emitter.

By developing a next generation theranostic pair with a novel compound, 89Zr/227Th-Lumi-PSMAUrea, which enables sensitive and high contrast PET imaging with 89Zr and exquisitely potent high-absorbed dose alpha particle therapy with 227Th, we seek to generate further safety and efficacy data in order to translate 89Zr-Lumi-PSMAUrea for first-in-man studies. 89Zr-Lumi-PSMAUrea PET imaging will precisely guide and predict 227Th-Lumi-PSMAUrea therapy to eradicate prostate malignancy.