What is “Translational Research?”

Translational research is the novel application of what scientists learn in the laboratory about the biology of a disease to the care of patients with that disease. This type of research tends to be highly innovative and “cutting edge.” Some of the most important advances to cancer treatment have occurred because of translational research.

Translational research is actually a process. Scientists conduct “basic” research (also called “bench” research) in the laboratory to understand the biology of cancer. Their results form the basis for clinical trials designed to improve the treatment of cancer patients (so-called “bench-to-bedside” research). The trials not only indicate whether a treatment is safe and effective, but also whether the laboratory models accurately reflect what happens in the patient. In addition a trial may reveal unforeseen information about how patients’ bodies react to a treatment or new vulnerabilities in the cancer. This feedback sparks more basic research (“bedside-to-bench”). The continual cycling of new information between basic research and clinical studies is known as translational research.

The Route 66 Endometrial Cancer SPORE team was selected by the National Cancer Institute (NCI) to receive an $11.6 million Specialized Program of Research Excellence (SPORE) grant to focus on translational research in endometrial cancer. The projects supported by this five-year award are described here.

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

Clinical Co-Leader: Kathleen Moore, MD, University of Oklahoma

Basic Co-Leader: Doris Benbrook, PhD, University of Oklahoma

The incidence and mortality of endometrial cancer has increased over the past few decades, and is predicted to continue rising. There is significant need for improved therapies with reduced toxicity for women with endometrial cancers that are advanced, recurrent or refractory to standard of care. Endometrial cancer is a heterogeneous disease that has been classified into molecular profile categories with different degrees of patient prognosis. Across these categories, endometrial cancer has the highest rates of mutations in heat shock protein A (HSPA) 5, 8 and 9 genes compared to other The Cancer Genome Atlas-studied cancers. The HSPA5, HSPA8 and HSPA9 genes encode chaperone proteins, Grp78, hsc70 and mortalin, respectively, which become elevated during carcinogenesis to bind and modulate oncoproteins in a way that assures cancer cell survival. Thus, these chaperone/oncoprotein complexes represent differential targets present at higher levels in cancer cells compared to healthy cells. We developed a drug, SHetA2 (NSC 726189), which disrupts these complexes.

SHetA2 induces growth arrest, altered metabolism, mitophagy and cell death in endometrial cancer cells, while the effects on healthy cells is limited to G1 cell cycle arrest. Preclinical studies found lack of SHetA2 toxicity, and this drug is now in a Phase 1 clinical trial in advanced, recurrent or persistent gynecologic cancers (NCT04928508). In vivo studies revealed that SHetA2 has complementary activities and efficacies with paclitaxel and cyclin dependent kinase (CDK4/6) inhibitors. In this project, we hypothesize that SHetA2 will safely reduce endometrial cancer tumor burden and complement the efficacies of paclitaxel and CDK4/6 inhibitors without increasing toxicity; the mechanism will be mediated through SHetA2 disruption of HSPA/client protein complexes; and the treatment efficacies will be modulated by mutations in PTEN and TP53 genes.

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.

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

Clinical Co-Leaders: David Mutch, MD and Matthew Powell, MD

Basic Co-Leader: Katherine Fuh, MD, 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.

The clinical trial data from Aim 1 will form the foundation of a future Phase II trial of batiraxcept plus paclitaxel in USC and G3 EEC patients. The data from Exploratory Aim 2 may allow us to develop a metabolic biomarker that can predict sensitivity to this drug combination and/or provide insight into the metabolic processes involved in tumors that do not respond to this drug combination. The data from Aim 3 will provide key mechanistic data to support a future clinical trial combining batiraxcept with bevacizumab. In the long term, this work will allow us to optimize and personalize treatment for patients with aggressive uterine cancer types. Our team is well-positioned to test our central hypothesis in clinical and experimental studies.

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

Clinical Co-Leader: Andrea Hagemann, MD

Basic Co-Leader: Kimberly Leslie, MD, University of New Mexico

Up to 90% of the ~65,000 women diagnosed with endometrial cancer each year in the U.S. are overweight or obese, and up to 60% of endometrial cancer cases are attributed to obesity. This is, in large part, because obesity promotes development of atypical endometrial hyperplasia (AEH), a precursor of grade 1 endometrial cancer. If diagnosed at one of these stages, a patient can be treated with hysterectomy, which is 100% effective in preventing/curing endometrial cancer. However, hysterectomy is often unacceptable to premenopausal women who would like to retain fertility. Instead, such patients are commonly treated with progestin, most commonly via a levonorgestrel-releasing intrauterine device. However, up to 41% of women on progestin eventually experience relapse and require a hysterectomy. Moreover, fewer than 12% of women who choose this option go on to have a live birth, likely because obesity and the commonly co-occurring insulin resistance impair fertility. As bariatric surgery can also reverse AEH and grade 1 endometrial cancer, an ideal treatment for premenopausal women desiring future fertility would be to simultaneously provide a progestin IUD along with an effective weight loss strategy.

This Early Detection, Prevention and Population Science project includes a randomized controlled trial testing the overall hypothesis that combined treatment with progestin and either therapeutic or behavioral weight loss interventions leads to greater uterine preservation than progestin use alone. 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.

Career Enhancement Program (CEP)

Co-Directors: David Mutch, MD; Doris Benbrook, PhD, University of Oklahoma; and, Carolyn Muller, MD, University of New Mexico

Program Application Information

The call for proposals for the first cycle of the Route 66 Endometrial Cancer SPORE Career Enhancement Program will be posted in fall 2023, tentatively. For additional information, please contact Linda Odibo, RN, MN, SPORE Administrator ([email protected]).

SPORE CEP Overview

The goal of the Career Enhancement Program (CEP) is to recruit and support early career and established investigators in translational endometrial cancer research. The CEP builds upon existing productive collaborations between outstanding researchers with expertise in translational endometrial cancer at Washington University, University of New Mexico, and University of Oklahoma. We will further enhance these collaborations by providing funding support, didactic training, career development and mentoring to new investigators in the field.

The CEP will pursue the following specific aims:

1) Recruit and support the careers of investigators new to endometrial cancer research;

2) Mentor and advise faculty researchers in translational endometrial cancer research;

3) Foster collaborations with partner institutions and other endometrial SPORE institutions, and

4) Promote diverse, equitable, and inclusive participation in endometrial cancer research.

Successful completion of these aims will support new investigators, improve our understanding of the spectrum of endometrial cancer, and develop new approaches for early detection, prevention, and treatment of this prevalent cancer. Our ultimate goal is to build a strong inclusive CEP program that mentors investigators to achieve successful careers in translational endometrial cancer research with the skills to develop an independent SPORE project and vibrant research careers.

Developmental Research Program (DRP)

Director: Kimberly Leslie, MD, University of New Mexico

Co-Directors: Dineo Khabele, MD and Kathleen Moore, MD, University of Oklahoma

Program Application Information

The call for proposals for the first cycle of the Route 66 Endometrial Cancer SPORE Developmental Research Program will be posted in fall 2023, tentatively. For additional information, please contact Linda Odibo, RN, MN, SPORE Administrator ([email protected]).

SPORE DRP Overview

The overall goals of the Route 66 Endometrial Cancer SPORE Developmental Research Program (DRP) are to support innovative, early-stage research in endometrial cancer, to develop pilot projects to the point of inclusion as full SPORE projects, to increase the number of investigators committed to endometrial cancer, and to diversify the workforce.

The DRP provides one- to two-year pilot funding for projects in basic, translational, clinical, epidemiologic, and cancer prevention and control research. The DRP is open to all three participating institutions in the SPORE: Washington University in St. Louis, University of Oklahoma, and University of New Mexico.

As a result of the DRP, bold new ideas in endometrial cancer research are funded at the pilot stage and developed to lead to new treatment or prevention strategies. We fully anticipate that one or more DRP projects will be elevated to full SPORE projects in the next funding period. Additionally, new investigators will leverage DRP support to develop their projects, obtain preliminary data, and secure external funding and thus establish their careers in endometrial cancer research. Finally, established investigators who are new to the field will apply their knowledge and expertise to the field of endometrial cancer.