SPORE in Endometrial Cancer

Principal Investigators: David Mutch, M.D., Washington University in St. Louis; Doris Benbrook, PhD, University of Oklahoma; and, Kimberly Leslie, M.D., University of New Mexico

The Route 66 Endometrial Cancer Specialized Programs of Research Excellence (SPORE) brings together interactive research teams from several institutions to create a dynamic translational research program aimed at developing and testing new strategies to prevent and treat endometrial cancer. The Route 66 Endometrial Cancer SPORE includes three translational research projects:

Project 1: Targeting HSPA Proteins in Advanced and Recurrent Endometrial Cancer Therapy

• Clinical Co-Leader: Kathleen Moore, M.D., University of Oklahoma
• Basic Co-Leader: Doris Benbrook, PhD, University of Oklahoma

The outcome is anticipated to identify biomarkers predictive of which patients will most likely benefit from SHetA2-based therapies, and provide justification and data for development of a randomized Phase 3 trial of a SHetA2 combination anticipated to have an improved therapeutic window over current therapy.

View Project 1

Project 2: Inhibiting AXL to Improve Treatment Response in Endometrial Cancer

• Clinical Co-Leaders: David Mutch, M.D. and Matthew Powell, M.D., Washington University in St. Louis
• Basic Co-Leader: Katherine Fuh, M.D., PhD, University of California San Francisco

The prognosis for the aggressive histologies in uterine cancer patients is low. This is likely due to lack of identification of pathways specific to uterine serous cancer or high-grade endometrioid tumors specifically. Our data suggest that the AXL pathway is highly expressed in uterine serous (USC) and grade 3 endometrioid endometrial cancer (G3 EEC) is associated with worse survival. We have recently shown that high-affinity, highly-selective inhibitor of AXL, AVB-500 (now known as batiraxcept), can improve response to paclitaxel in USC and G3 EEC. Additionally, there is developing data that AXL expression is correlated with the highly glycolytic phenotype, and this correlation with glycolysis may allow us to determine which tumors can respond better to AXL inhibition. Furthermore, published data supports that AXL regulates VEGF-A, and our preclinical data supports that inhibition of AXL can improve response to the anti-angiogenic agent, bevacizumab. Our central hypothesis is that inhibiting GAS6/AXL with AVB-500 will improve response to standard of care treatment. We will expand to test this hypothesis in three specific aims.

• Aim 1: Determine the safety and tolerability of combining batiraxcept with standard-of-care paclitaxel in patients with recurrent, aggressive endometrial cancer histologies (USC and G3 EEC).
• Exploratory Aim 2: Identify tissue and blood markers that correlate with response to treatment.
• Aim 3: Determine the mechanisms by which batiraxcept improves response to the standard-of-care anti-angiogenic bevacizumab.

View Project 2

Project 3: Primary Prevention and Uterine Preservation in Premenopausal Women with Obesity and Endometrial Hyperplasia/Cancer

• Clinical Co-Leader: Andrea Hagemann, M.D., Washington University in St. Louis
• Basic Co-Leader: Kimberly Leslie, M.D., University of New Mexico

Our aim is to determine the efficacy of progestin plus a behavioral weight loss intervention to allow uterine preservation and cancer prevention in premenopausal women with AEH or grade 1 endometrial cancer. Our exploratory aim is to identify biomarkers that reflect response to progestin plus weight loss. If this project identifies effective strategies, they can be widely implemented to allow premenopausal women with AEH or grade 1 endometrial cancer to both avoid cancer and preserve their uterus for future fertility.

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More Resources

These projects are supported by three shared resources: an administrative core; a biostatistics and bioinformatics core; and, a biospecimens, metabolomics, and pathology core. This SPORE also supports a Career Enhancement Program to recruit and mentor new investigators in translational endometrial cancer research and a Developmental Research Program to support innovative translational concepts.

Contact

For additional information about the Route 66 Endometrial Cancer SPORE, contact Doris Benbrook, PhD, (Doris-Benbrook@ouhsc.edu), David Mutch, M.D., (mutchd@wustl.edu), or Veronica Dave, PhD, SPORE Administrator (vdave@wustl.edu)