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Mayo Clinic SPORE in Ovarian Cancer

Mayo Clinic

Principal Investigators

Headshot of Scott Kaufmann

 

Scott Kaufmann, M.D., Ph.D.
Professor of Medicine and Pharmacology
Co-Leader, Experimental Therapeutics Program
Mayo Clinic
Gonda 19-212
Mayo Clinic/200 First Street S.W.
Rochester, MN 55905
507-284-8950

Headshot of Jamie Nadine Bakkum-Gamez, MD

 

Jamie Nadine Bakkum-Gamez, M.D.
Professor of Obstetrics and Gynecology
Co-Leader, Breast and Gynecologic Cancer Translational Science Team
Mayo Clinic
Gonda 19-212
Mayo Clinic/200 First Street S.W.
Rochester, MN 55905
507-538-5867

Overview

The overarching goal of the Mayo Clinic Specialized Program of Research Excellence (SPORE) in Ovarian Cancer is to improve the diagnosis and treatment of ovarian, fallopian tube and primary peritoneal cancer (called “ovarian cancer” below) through interdisciplinary preclinical and clinical research. The SPORE includes four translational research projects:

  • Project 1: Personalized Vaccines Targeting Cryptic Antigens in Ovarian Cancer 
  • Project 2: Targeting a Metabolic Pathway to Treat Ovarian Cancer
  • Project 3: Antibody-drug conjugates for Ovarian Cancer with a suboptimal response to platinum-based neoadjuvant therapy 
  • Project 4: Mitotic MTH1 Inhibitors for Platinum-Resistant Ovarian Cancer 

Additional research is conducted by investigators who receive support through the Career Enhancement and Developmental Research Programs. The Cores facilitate this translational ovarian cancer research by providing annotated specimens of ovarian cancers and normal controls required for the laboratory studies (the Biospecimens/Patient Registry Core), the statistical and bioinformatic expertise for analysis of the laboratory and clinical results (the Biostatistics and Bioinformatics Core), and appropriate cancer models for the safe and efficient testing of potential new therapies before transfer to the clinic (Cancer Models Core).

SPORE investigators work together as a team to meet the goals of the program and interact with investigators from SPOREs and ovarian cancer research groups at other institutions to improve therapeutic outcomes for patients.

Project 1: Personalized Vaccines Targeting Cryptic Antigens in Ovarian Cancer

Project Co-Leaders

Specific Aims

Although most people diagnosed with high grade serous ovarian cancer (HGSOC) initially respond to platinum-based chemotherapy, most also eventually develop treatment-resistant disease, underscoring the need for new therapies. Studies have shown that patients whose tumors contain higher levels of immune cells, including CD3+ and CD8+ T cells, tend to have better outcomes, suggesting that strengthening the body's immune response could improve treatment. However, the tumor targets recognized by these immune cells remain poorly understood. Unlike many other cancers, HGSOC rarely produces mutation-derived neoantigens that can be targeted by immunotherapy. The Project 1 team has identified hundreds of "cryptic" antigens—peptides produced from regions of the genome typically considered noncoding—that are displayed by HGSOC tumor cells and can stimulate strong immune responses. To build on these findings, the Project 1 team will now investigate how these cryptic antigens contribute to anti-tumor immunity and evaluate whether they can serve as personalized vaccine targets.

Project 1 includes laboratory studies to define the role of cryptic antigens in HGSOC immunity and a first-in-human Phase I clinical trial testing the safety of a personalized peptide vaccine in HGSOC patients with correlative assessment of immunologic response to cryptic antigen vaccination. Results from Project 1 could establish cryptic antigens as a new class of immunotherapy targets and support the development of more effective treatments for people with ovarian cancer via an overarching goal of a vaccination strategy designed to prevent HGSOC recurrence.

Project 2: Targeting a Metabolic Pathway to Treat Ovarian Cancer

Project Co-Leaders

Specific Aims

Although many HGSOCs initially respond to PARP inhibitors (PARPi) due to defects in DNA repair pathways, most patients eventually develop treatment resistance. Project 2 aims to enhance PARPi sensitivity by targeting nicotinamide phosphoribosyltransferase (NAMPT), a key enzyme required for production of NAD+. NAMPT is a metabolite that supports DNA repair and cancer cell survival. Using genome-wide CRISPR screening, the Project 2 team identified genetic alterations, including loss of RAD51C and PTEN, that increase tumor sensitivity to NAMPT inhibitors (NAMPTi). These alterations occur in up to 25% of HGSOC cases and may help identify patients most likely to benefit from this approach. Preclinical studies demonstrated that NAMPT inhibition produced strong antitumor activity, especially when combined with the PARPi olaparib. This combination induced durable tumor regressions in vivo, including in patient-derived xenograft HGSOC models resistant to PARPis alone. 

Building on these promising findings, the Project 2 team will identify additional biomarkers of NAMPTi + PARPi response beyond RAD51C and PTEN deficiency, evaluate the combination therapy in multiple preclinical models, and conduct a Phase I clinical trial of a NAMPTi and olaparib to assess safety, tolerability, and biomarker-guided patient selection. This work could establish a new precision medicine strategy for patients with HGSOC and improve treatment options for those with PARPi-resistant disease.

Project 3: Antibody-drug conjugates for ovarian cancer with a suboptimal response to neoadjuvant platinum-based chemotherapy (NApCT)

Project Co-Leaders

Specific Aims

The current standard of care for advanced-stage HGSOC includes neoadjuvant platinum-based chemotherapy (NApCT) before interval debulking surgery (IDS). However, about one-third of patients do not respond well enough to NApCT to benefit from surgery, a finding that is associated with worse survival and leaves patients with few effective treatment options. The Project 3 team will evaluate whether switching systemic therapy earlier in the course of HGSOC treatment to antibody-drug conjugates (ADCs) carrying topoisomerase I (TOP1) inhibitors (TOP1-ADCs), such as trastuzumab deruxtecan (T-DXd) and sacituzumab tirumotecan (sac-TMT), can improve outcomes for patients whose tumors show poor response to initial NApCT. Early clinical studies suggest that ADCs, which are designed to deliver potent anti-cancer agents directly to tumor cells while limiting exposure to healthy tissues, are active in platinum-resistant ovarian cancer and may stimulate anti-tumor immune responses. 

In Project 3, patients with HGSOC identified as poor responders to NApCT based on established biomarkers will receive T-DXd for HER2-positive tumors or sac-TMT for HER2-low or HER2-negative tumors. The Project 3 team will measure tumor response, success of IDS, progression-free survival, overall survival, circulating cell-free tumor DNA and various immune parameters to establish efficacy, mechanisms of action, and biomarker strategies for TOP1-ADCs in NApCT resistant HGSOC. Collectively, Project 3 aims to develop a more effective, personalized treatment strategy for patients with NApCT resistant HGSOC and guide future combination therapies.

Project 4: Mitotic MTH1 Inhibitors for Platinum-Resistant Ovarian Cancer

Project Co-Leaders

Specific Aims

Ovarian cancer that recurs after treatment and no longer responds to platinum-based chemotherapy remains one of the greatest treatment challenges, underscoring the need for new therapies. Project 4 focuses on a promising targeted drug, karonudib (OXC-101), which blocks the activity of MTH1, an enzyme that is critical for survival of cancer cells due to their elevated oxidative stress relative to normal cells. By inhibiting MTH1, karonudib causes oxidized nucleotides to accumulate in cancer cells, leading to cancer cell death while largely sparing healthy tissue. The Project 4 team has demonstrated that karonudib is effective against both platinum-sensitive and platinum-resistant ovarian cancer cells and, when combined with paclitaxel, produces greater tumor shrinkage and longer survival in patient-derived xenograft (PDX) models of HGSOC. Additionally, a recent Phase I clinical trial demonstrated that the orally administered karonudib is well tolerated in patients with advanced solid tumors, supporting further clinical development. 

Project 4 will evaluate the effectiveness of karonudib plus paclitaxel across diverse ovarian cancer preclinical models, develop ovarian cancer cell line and PDX models that are resistant to karonudib to determine why some tumors respond while others do not, and conduct a Phase Ib clinical trial combining karonudib and paclitaxel in patients with platinum-resistant HGSOC. This will be the first Phase Ib clinical trial of karonudib in any solid tumor and the first North American karonudib trial. Together, Project 4 aims to advance a first-in-class targeted therapy and identify biomarkers that can help identify patients most likely to benefit from this therapy.

Administrative Core

Core Co-Directors

Specific Aims

The overall goals of the Mayo Clinic SPORE in Ovarian Cancer are to stimulate innovative research in ovarian cancer and to expedite the translation of discoveries into new and better methods of prevention, detection and treatment of this disease. The Administrative Core provides organizational and communications support for the SPORE leadership that helps to integrate the translational research Projects, scientific Cores, Developmental Research Program (DRP) and Career Enhancement Program (CEP). The Core also serves as the administrative liaison between this SPORE, the NCI SPORE Program, other Mayo SPOREs, and external collaborators.

Biospecimens and Patient Registry Core

Core Co-Directors

Specific Aims

The goal of the Biospecimens and Patient Registry Core is to provide investigators in the Ovarian SPORE with high quality patient data, DNA, RNA, blood products, and tissues (normal and malignant) from consented patients with ovarian cancer. This Core is integrated with existing tissue-oriented Mayo Clinic Comprehensive Cancer Center and Institutional shared resources, including:

  •  the Mayo Clinic Tissue Registry, which has formalin-fixed paraffin-embedded tissue dating back over a century and digital images spanning up to 25 years;
  • the Pathology Research Core, which provides expertise, collaborative support, and service for immunohistochemistry, in situ hybridization, tissue microarray construction, and digital imaging;
  • the Cytogenetics Core, which has expertise in establishing, validating, and scoring fluorescence in situ hybridization studies; and
  • the Biospecimens Accessioning and Processing Core, which provides standardized processing of blood and frozen tissue collected explicitly for research. 

To provide clinical annotation needed to maximize the potential use of tissue specimens in translational research, risk factor questionnaires, clinical records, and pathology review are incorporated into the Core. Built on a frozen tissue repository containing ovarian cancer samples from over 4700 patients, the Core works closely with the Biostatistics and Bioinformatics Core to provide tissue resources needed for the success of the translational research projects as well as CEP and DRP awardees.

Biostatistics and Bioinformatics Core

Core Director

The Ovarian SPORE Biostatistics and Bioinformatics Core provides statistical collaboration, data management assistance and bioinformatics support for each of the SPORE translational projects, the DRP and CEP, and the other Cores to help assure that research in this SPORE is carried out in an efficient, effective, and rigorous manner. The Biostatistics and Bioinformatics Core provides each SPORE investigator access to statistical and bioinformatic expertise that includes collaborative development of study designs and analysis plans, state-of-the-art data analysis and interpretation, and data management resources. By serving as a repository for the clinical and multi-omic data associated with each clinical specimen and cancer model, this Core complements and assists the efforts of the Biospecimens and Patient Registry, and Cancer Models Cores.

Cancer Models Core

Core Director

S. John Weroha, M.D., Ph.D.

Specific Aims

The goals of the Cancer Models Core are to improve understanding of ovarian cancer and enhance the development of novel therapies by providing clinically relevant models that will be highly translatable, thereby helping investigators bring innovative therapeutic concepts from the "bench to the bedside" in as safe a manner as possible. To this end, we will employ an array of cancer models, including:

  •   cell culture-based ex vivo models, 
  •   in vivo models developed from our "living tumor bank" of over 650 distinct patient-derived      xenografts (PDXs), and 
  •  newly-developed cancer model methods, including additional in vitro modeling of cancer using microfluidic devices and innovative engraftment approaches for tumors that have historically been difficult to engraft in vivo. 

PDX models recapitulate the histologic, molecular biology, pattern of spread and drug response characteristics of the source tumors when grown as orthotopic models in immunodeficient mice. DRP and CEP awardees have access to these models as needed. In collaboration with the Biospecimens and Patient Registry, and Biostatistics Cores, we will select appropriate models based on source tumor or PDX characteristics and utilize them in experiments to evaluate the impact of treatment ex vivo or in vivo.

Developmental Research Program

Program Co-Directors

Specific Aims

The Developmental Research Program (DRP) is designed to provide pilot project funding to test intriguing new ideas for which there is a strong rationale but limited experimental evidence. Based on evaluations of peer reviewers, at least four of the most compelling projects per year are funded with the expectation that successful projects will be able to compete for further funding from extramural sources with the additional data generated through support of the DRP.

Career Enhancement Program

Program Co-Directors

Specific Aims

The goal of the CEP is to provide mentored training in translational ovarian cancer research for early career investigators and established investigators who are transitioning their research focus to ovarian cancer. Limited to 1-2 awardees, this program selects candidates based on past accomplishments and provides coaching to help awardees jumpstart their independent ovarian cancer research careers.

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