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Last Updated: 10/10/18

Mayo Clinic SPORE in Ovarian Cancer

Mayo Clinic, Rochester

PRINCIPAL INVESTIGATOR CONTACT INFORMATION

Scott H. Kaufmann, M.D., PhD
Professor
Department of Pharmacology
Mayo Clinic Foundation
Guggenheim Room 1328
200 First St., Southwest
Rochester, MN 55905
Phone: (507) 284-8950
Fax: (507) 284-3906
Email: Kaufmann.Scott@Mayo.edu

OVERVIEW

Scott H. Kaufmann, M.D., Ph.D., Principal Investigator
Lynn C. Hartmann, M.D., SPORE Co-Leader

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) and to better understand susceptibility to these cancers. The SPORE includes four major translational research projects in ovarian cancer, a developmental research (pilot project) program, and a career enhancement program. The Ovarian SPORE uses an interdisciplinary approach to meet its objectives. Project co-investigators have expertise in basic research, population science, and clinical investigation. The main projects are:

Project 1: Novel Determinants of PARP Inhibitor Sensitivity in Ovarian Cancer
Project 2: Targeting Protein Kinase Ci for Ovarian Cancer Therapy
Project 3: Metformin as a Metabolic Therapeutic in Ovarian Cancer
Project 4: Development of a Th17-Inducing Dendritic Cell Vaccine for Ovarian Cancer

The cores provide support for the main research projects, developmental research projects, and career enhancement projects to facilitate ovarian cancer translational research. In particular, the Biospecimens Core (Core B) provides annotated specimens of ovarian cancers and normal controls required for the laboratory studies, the Biostatistics Core (Core C) provides the statistical and bioinformatic expertise for analysis of the laboratory and clinical results, and the Animal Models Core (Core D) provides appropriate animals models for the safe and efficient testing of potential new therapies before they are transferred to the clinic. The Administrative Core (Core A) provides scientific and fiscal oversight for the program. SPORE investigators work together as a team to meet the goals of the program and also interact with investigators from SPOREs and ovarian cancer research groups at other institutions to improve therapeutic outcomes for patients.

PROJECT 1: Novel Determinants of PARP Inhibitor Sensitivity in Ovarian Cancer

Scott H. Kaufmann, M.D., Ph.D., co-Leader
Andrea E. Wahner Hendrickson, M.D., co-Leader
Larry M. Karnitz, co-Investigator

Poly(ADP-ribose) polymerase inhibitors (PARPis) have shown promising activity in homologous recombination- (HR-) deficient preclinical models and response rates of 30-60% in BRCA1 or BRCA2 (BRCA1/2) mutation carriers with platinum-sensitive relapsed ovarian cancer. These results led to recent regulatory approval of the PARPi olaparib for ovarian cancer in the U.S. and Europe. Notably, 20-30% of ovarian cancers without BRCA1/2 mutations also respond. It is currently unclear how to best identify patients whose ovarian cancers will respond to these agents. Project 1 is designed to help address this issue by assessing biomarkers of response in both BRCA1/2-mutant and BRCA1/2-wildtype ovarian cancers. Building on our results showing that i) downregulation of nonhomologous end-joining (NHEJ) repair pathway proteins markedly diminishes PARPi sensitivity in vitro, ii) BRCA2-mutant ovarian cancer clones selected for PARPi resistance exhibit marked changes in certain repair proteins, and iii) a number of repair proteins show highly variable expression in pretreatment samples of BRCA1/2-mutant ovarian cancers, we propose to further examine the relationship between differences in repair protein expression and PARPi resistance in preclinical studies and in pretreatment biopsies from a phase 2 trial of single-agent rucaparib in patients with platinum-sensitive, relapsed ovarian cancer (ARIEL 2, ClinicalTrials.gov identifier NCT01891344). Assays in the clinical samples are designed to test four complementary explanations for PARPi resistance, including reversion mutations in BRCA1/2, low NHEJ pathway protein expression, variation in PARP1 levels, and compensatory changes in other DNA repair pathways. Importantly, this rucaparib study was specifically designed to enroll participants with both BRCA1/2-mutant and BRCA1/2-wildtype ovarian cancers in an attempt to better understand the determinants of response in both groups.

PROJECT 2: Targeting Protein Kinas Cι for Ovarian Cancer Therapye

Alan P. Fields, Ph.D., co-Leader
Aminah Jatoi, M.D., co-Leader
Nicole Murray, Ph.D., co-Leader

The 3q26 region of chromosome 3 is known to be amplified in >70% of high-grade serous ovarian cancers (HGSOCs), the most common and most lethal subtype. Previous work from the Fields lab has provided the first evidence that Protein Kinase C iota (PKCι), which is located in the middle of this amplicon, is an oncogene. Working with both bulk ovarian cancer cells and tumor initiating cells (TICs), which are well established as a source of resistance in ovarian cancers and other malignancies, the Fields lab has demonstrated that ovarian cancer cell proliferation and survival is driven by a PKCι-initiated signaling pathway that is unique to ovarian cancer as compared to other cancers in which PKCι is amplified (e.g., nonsmall cell lung cancer). Moreover, the Fields laboratory has partnered with collaborators to identify and characterize highly selective PKCι inhibitors, including a lead compound that is moving toward a first-in-human trial with an expansion cohort in ovarian cancer. Building on these results, the investigators propose to: 1) dissect the mechanism by which PKCι regulates ovarian cancer TIC behavior and assess the effect of PKCι inhibition on the ovarian cancer TIC phenotype; 2) assess the effect of PKCι inhibition on signaling and growth of HGSOC cell lines and validate potential pharmacodynamic and predictive biomarkers of PKCι inhibitors in patient-derived ovarian cancer xenografts in vivo; and 3) in humans, assess the clinical activity of the specific PKCι inhibitor auranofin in combination with the mTOR inhibitor sirolimus in a phase 2 trial in relapsed ovarian cancer as well as the ability of 3q26 amplification or PKCι expression in predicting response.

PROJECT 3: Metformin as a Metabolic Therapeutic in Ovarian Cancer

Ernst Lengyel, M.D., Ph.D., co-Leader
Iris Romero, M.D., co-Leader
Gini Fleming, M.D., co-Leader
S. Diane Yamada, M.D., co-Investigator

Administration of metformin, an oral biguanide prescribed for diabetic patients to improve glycemic control, was shown in independent retrospective analyses by investigators at the University of Chicago and Mayo Clinic to be associated with improved progression-free survival of diabetic ovarian cancer patients compared to diabetic ovarian cancer patients treated with other agents. Our subsequent in vitro studies, using ovarian cancer cell lines and an organotypic 3D model of ovarian cancer metastasis, suggest that metformin inhibits tumor growth, induces apoptosis, and sensitizes tumor cells to platinum/paclitaxel chemotherapy by modifying ovarian cancer cell metabolism. We propose to i) elucidate the mechanisms by which metformin affects tumor cell growth and chemoresistance, focusing on both tumor and stromal cells, ii) use patient-derived ovarian cancer xenografts to study pharmacodynamic markers of metformin action, and iii) use prospectively collected serum and tissue samples from a randomized phase 2 clinical trial of standard therapy ± metformin, including paired samples from patients treated in the neoadjuvant setting, to understand the mechanisms of metformin antineoplastic action in the clinical setting. The accompanying clinical trial (ClinicalTrials.gov identifier NCT02122185) is the first clinical trial to examine the impact of metformin on standard ovarian cancer therapy (surgery and adjuvant or neoadjuvant chemotherapy) as part of initial therapy, a setting in which we hypothesize metformin will have the largest impact.

PROJECT 4: Development of a Th17-Inducing Dendritic Cell Vaccine for Ovarian Cancer

Keith L. Knutson, Ph.D., co-Leader
Matthew Block, M.D., Ph.D., co-Leader
Martin Cannon, Ph.D., co-Investigator

Leaders of this project and others have shown that the ability of ovarian cancer to evade host immune responses is due in large part to the influence of regulatory T cells (Tregs), which are CD4+ T cells that cause anergy of ovarian cancer-reactive T helper 1 (Th1) and CD8+ T cells, as well as immunosuppressive changes in macrophages and dendritic cells (DCs). Tregs are induced not only during endogenous anti-ovarian cancer immune responses, but also in the context of anti-ovarian cancer vaccines, thereby limiting vaccine efficacy. However, the presence of T helper 17 (Th17) cells promotes a proinflammatory antigen-specific immune response and is associated with reduced levels of Tregs. The project team has recently described a novel strategy of ex vivo DC maturation that leads to a robust antigen-specific Th17 response. In a murine model of ovarian cancer, Th17-inducing DCs stimulated anti-ovarian cancer Th17 immune responses, a dramatic reduction in Tregs, and durable ovarian cancer remissions. In parallel studies, the team also identified a novel ovarian cancer antigen, the folate receptor alpha (FRa), that is overexpressed on the vast majority of human (and mouse) ovarian cancer tumors and is associated with worse clinical outcomes. The investigators have identified antigenic peptides from FRa; and a clinical study testing these peptides in a therapeutic vaccine has been completed. Building on these results, the project team proposed to 1) determine the immune effectors underpinning the anti-tumor efficacy of Th17-inducing cancer vaccines, 2) assess whether induction of Th17 immune responses targeting ovarian cancer antigens will overcome local tumor immune suppression by inhibiting Treg generation and modulating infiltrating myeloid cell function, and 3) complete a recently opened clinical trial (ClinicalTrials.gov identifier NCT02111941) to determine whether FRa-specific Th17 T cell responses can be safely generated in OvCa patients following their adjuvant chemotherapy. Importantly, this trial will be performed in the setting of minimal residual disease, where immunotherapy might be most effective.

CORE A: Administrative Core

Scott H. Kaufmann, M.D., Ph.D., co-Director
Lynn C. Hartmann, M.D., co-Director

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, research projects, scientific cores and developmental programs [Developmental Research Program (DRP) and Career Enhancement Program (CEP)]. Specifically, the Administrative Core will: 1) provide leadership and organizational support to SPORE investigators; 2) oversee formal procedures for scientific review of SPORE research projects; 3) oversee and facilitate the efforts of all cores; 4) manage and coordinate SPORE fiscal activities; 5) monitor accrual to all SPORE clinical trials, population research studies and biospecimen collections; 6) provide guidance and administrative support to the DRP and CEP leadership; 7) facilitate the activities of the Executive Committee and implement its decisions; 8) facilitate engagement of the SPORE advocates; 9) facilitate reviews of the SPORE by the External Advisory Board and Internal Scientific Advisory Committee; 10) organize monthly SPORE seminars, scientific meetings and the annual retreat; 11) assure ongoing integration of the Ovarian SPORE with the Mayo Clinic Cancer Center and its Women’s Cancer Program; and 12) serve as the administrative liaison between the Mayo Ovarian SPORE, the NCI SPORE Program, other Mayo SPOREs, and external collaborators.

CORE B: Biospecimens Core

Gary Keeney, M.D., Director
Mark E. Sherman, M.D., co-Director
Sun-Hee Lee, Ph.D., co-Investigator
Debra A. Bell, M.D., Consultant
Thomas J. Flotte, M.D., Consultant

The goal of the Biospecimens and Patient Registry Core is to provide investigators in the Ovarian SPORE high quality patient data, DNA, RNA, blood products, and tissues (normal and malignant) from consented patients with ovarian, fallopian tube, or primary peritoneal carcinoma and to make these resources available for future studies. The Mayo Clinic has a strong tradition of ethically sound support of research that links tissue acquisition and patient data records. Paraffin embedded tissues, histological slides, and associated patient charts from surgeries performed since the first decade of the 1900's are maintained in Mayo’s Tissue Registry and the Mayo Archives. Today, the Pathology Research Core (PRC) of the Mayo Clinic Cancer Center is a resource of expertise, collaborative support, and service for immunohistochemistry, in situ hybridization, tissue microarray construction, and digital imaging. Similarly, the Biospecimens Accessioning and Processing (BAP) core is the primary site of accessioning and standardized processing of blood and frozen tissue collected explicitly for research from all three Mayo sites. The Cytogenetics Core has expertise in establishing, validating, and scoring fluorescence in situ hybridization (FISH) studies. Core B will be integrated with these existing tissue-oriented Cancer Center shared resources and other scientific Cores of this SPORE to provide a coordinated, centralized, dedicated program for standardized collection, accessioning, processing, morphological classification and evaluation of biospecimens and patient data from fully consented ovarian cancer patients. Thorough clinical annotation is required to maximize the potential use of tissue specimens in translational research; therefore, risk factor questionnaires, clinical records, and pathology review are incorporated into the Core. Research services, including pathologic review of tumor histology, tumor sectioning and quality control, blood processing, construction of tissue microarrays (TMAs), immunohistochemistry (IHC), and FISH will be provided to SPORE investigators. The Core will be closely coordinated with the Biostatistics Core to provide seamless linkage of clinical annotation with research specimens for data management and analyses.

CORE C: Biostatistics Core

Ann L. Oberg, Ph.D., Director
Hu Li, Ph.D., co-Investigator
Matthew Maurer, M.S., co-Investigator

The Ovarian SPORE Biostatistics Core provides statistical collaboration and data management support for each of the main SPORE projects, the Developmental Research and Career Enhancement projects, and the other Cores. The Biostatistics Core will assure each SPORE investigator access to statistical expertise that includes collaborative development of study designs and analysis plans, state-of-the-art data analysis and interpretation, data management resources, and abstract and manuscript preparation. The proposed projects span a wide range of approaches and analyses. In addition, Core members will continue to improve existing database infrastructure to support the activities of SPORE investigators. This Core complements and assists the efforts of the Biospecimens/Patient Registry Core by providing superior data management and experience with biospecimen registries. Through these collaborative activities, the Biostatistics Core will help assure that research in this SPORE is carried out in an efficient, effective, and rigorous manner.

CORE D: Animal Models Core

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

The goals of the Animal Models Core of the Mayo Clinic Ovarian SPORE 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 these treatments from the “bench to the bedside” in as safe a manner as possible. To this end, we will employ models developed from our large patient-derived xenograft (PDX) ‘living tumor-bank’ to develop novel therapies in three of the four Projects. These PDX models recapitulate the histologic, molecular and drug response characteristics of the source tumors as orthotopic models in SCID mice. Moreover, these models spread throughout the peritoneal cavity, including omentum, just like the human counterpart. In collaboration with the Biospecimens and Biostatistics Cores, we will select appropriate models based on source tumor (such as clinical parameters or germline genotypes) or PDX characteristics (such as drug sensitivity, mutation or gene expression profile) and expand them for use in experiments to evaluate treatment. In addition, we will collaborate with the fourth Project to provide multiple immunocompetent models, including models that have previously been instrumental in evaluating the role of dendritic cells in immune suppression in ovarian cancer in our previous funding period.