NCI Funds Eight SPORE Grants

NCI awarded eight new, competing and renewed grants as part of its funding for its Specialized Programs of Research Excellence. The grantees will receive $2,185,000 per year for five years.

Of the 36 applications submitted for the 2015 fiscal year—with the eight grants coming to a 22.2 percent success rate—four funded studies were brand new to the SPORE program and four were renewal applications. Each of the renewed grants included a new principal investigator or new multiple PIs.

“The SPORE program is 23 years old and has been evolving since day one, based upon recommendations for NCI advisory groups and the evolution of science, itself,” said Toby Hecht, associate director of the Translational Research Program in the NCI Division of Cancer Treatment and Diagnosis.

“We expect this evolution to continue to keep the program up-to-date and relevant,” said Hecht. “One interesting change that will be taking place this year is giving a funding incentive to awarded applications that include translational cancer research in qualified early detection, prevention, and population science projects—areas that are underrepresented in the NCI portfolio.”

The four new SPOREs and their lead investigators are:

• Wade Clapp, of Indiana University, and Kevin Shannon, of University of California, San Francisco, for developmental and hyperactive RAS tumors. This is the SPORE program’s first pathway-based grant.
  Clapp is the Richard L. Schreiner Professor, chairman of the Department of Pediatrics and a professor of microbiology at Indiana University. Shannon is the Auerback Distinguished Professor of Molecular Oncology in the UCSF Department of Pediatrics and an American Cancer Society Research Professor. He is also director of the UCSF Physician Scientist Scholar Program.
• Leif Bergsagel and Vincent Rajkumar, of the Mayo Clinic, in multiple myeloma. Bergsagel is co-director of the Hematologic Malignancies Program at the Mayo Clinic Comprehensive Cancer Center and a professor of medicine at the Mayo Clinic College of Medicine. Rajkumar is chair of the Myeloma Amyloidosis Dysproteinemia Group at the Mayo Clinic, chair of the Eastern Cooperative Oncology Group Myeloma Committee and co-chair of the International Myeloma Working Group.
• Roy Herbst, of Yale University, in lung cancer. Herbst is chief of Medical Oncology at Yale Cancer Center and Smilow Cancer Hospital, and associate director for translational research at Yale Cancer Center.
• Sue O’Dorisio, for the first and only SPORE grant in neuroendocrine tumors. O’Dorisio is a distinguished professor in pediatrics at the University of Iowa.

The developmental and hyperactive RAS tumor SPORE involves researchers at NCI’s Pediatric Branch and eight academic institutions. Its overall goal is to implement targeted treatments for tumors characterized by mutations of the NF1 tumor suppressor gene.

In contrast to most other SPORE efforts supported by the NCI, this project does not focus on a particular type of cancer. Persons with NF1 have a markedly increased incidence of developing specific tumors, which are frequently diagnosed in children, adolescents and young adults.

The program encompasses four integrated projects and three cores: administrative core, a biospecimen and pathology core, and an omics core. The main projects are:

Project 1: Molecular, Developmental, and Genetic Evaluation of Plexiform Neurofibromas to Inform Clinical Trials

Project 2: Targeted Therapies for Malignant Peripheral Nerve Sheath Tumors

Project 3: A High Content Clinical Trial of the MEK Inhibitor Trametinib in Juvenile Myelomonocytic Leukemia

Project 4: Subsequent Malignant Neoplasms Among NF1 Cancer Survivors

The program plans to re-purpose drugs that are being developed to block the biochemical effects of RAS gene mutations, which are found in about one-third of all cancers.

Because the protein made by the NF1 gene interacts directly with Ras and controls its activity, drugs that are being tested in cancers with RAS gene mutations should also be systematically evaluated in malignancies driven by NF1 inactivation, according to this project’s abstract.

The Mayo Clinic multiple myeloma SPORE includes four major translational research projects, a developmental research program, a career enhancement program, a biostatistics/bioinformatics core, a biospecimen core, and an administrative core. Project investigators are located at all three Mayo Clinic sites, in Arizona, Minnesota and Florida.

The main projects are:

Project 1: Oncolytic Virotherapy using Vesicular Stomatitis Virus

Project 2: Immunomodulatory Therapy with SMAC Mimetics

Project 3: MYC in Progression and Treatment

Project 4: Clonal Evolution

Journalist and Mayo Clinic Trustee Tom Brokaw will serve as a patient advocate to the SPORE. Brokaw was diagnosed with multiple myeloma at the Mayo Clinic in 2013.

The Yale SPORE in lung cancer seeks to improve overall survival by developing therapeutics and personalized prevention strategies based on targetable pathways involved in the progression of lung cancer and the acquisition of resistance to therapy.

The project has five specific aims:

1. Develop and test novel therapeutics by discovering the mechanisms underlying the response and resistance to anti-PD-1 and anti-B7-H1 (PD-L1) therapies;
2. Evaluate the potential of non-coding microRNAs as targeted therapies;
3. Understand and target the EGFR pathway in mutant/resistant lung cancer;
4. To develop and test the efficacy of a new personalized approach to gain-framed messaging to improve smoking cessation in Americans with asymptomatic lung nodules who continue to smoke; and
5. To develop new research directions and nurture the next generation of translational investigators in lung cancer through a developmental research program and a career development program.

The University of Iowa SPORE in neuroendocrine tumors includes four major projects and four cores that will explore the genetics of the tumors, their molecular makeup, and new approaches to diagnosis and treatment. This is the first and only SPORE grant to fund research on neuroendocrine tumors.

The main projects are:

1. Theranostics in Neuroendocrine Tumors
2. Molecular Mechanisms and Biomarkers of Neuroendocrine Tumors
3. Genetic Studies of IIeal Neuroendocrine Tumors
4. New Approaches to Improving the Effectiveness of Radionuclide Targeted Treatments in Neuroendocrine Tumors

More detail on the individual projects is available here.

The 2015 competing renewal SPOREs and their lead investigators are:

• William Catalona, in prostate cancer. Catalona is a professor in the Department of Urology at Northwestern University Feinberg School of Medicine, and is director of the Clinical Prostate Cancer Program at the Robert H. Lurie Comprehensive Cancer Center.
• Robert Ferris and Jennifer Grandis in head and neck cancer. This grant is co-funded by the National Institute of Dental and Craniofacial Research.

Ferris is vice-chair for clinical operations and chief of the Division of Head and Neck Surgery, as well as co-leader of the Cancer Immunology Program at the University of Pittsburgh Cancer Institute. Grandis is associate vice chancellor for clinical and translational research, director of the Clinical and Translational Science Institute, and a professor in the Department of Otolaryngology at the University of California, San Francisco.

• David McDermott and William Kaelin, of Dana Farber Cancer Institute, in kidney cancer.
  McDermott is the leader of the Dana Farber/Harvard Cancer Center Kidney Cancer Program and is director of the Biologic Therapy and Cutaneous Oncology Programs at Beth Israel Deaconess Medical Center, as well as an associate professor of medicine at Harvard Medical School.
  Kaelin currently serves as associate director of basic science at Dana-Farber/Harvard Cancer Center, and is a professor in the Department of Medicine at Dana-Farber and at the Brigham and Women’s Hospital.
• Scott Kaufmann, of the Mayo Clinic, in ovarian cancer.
  Kaufmann is chair of the Division of Oncology Research and associate director of the Medical Scientist Training Program at the Mayo Clinic College of Medicine, and co-chair of the Developmental Therapeutics Program at Mayo Clinic Cancer Center.

The Northwestern University Prostate Cancer SPORE aims to identify patients who have aggressive prostate cancer versus those who have indolent disease through population genetic studies; to develop therapies for castration-resistant prostate cancer, such as combination therapy to re-sensitize patients to androgen deprivation or novel molecular therapeutic approaches; and to develop and validate biomarkers that will avoid overtreatment of patients who receive a diagnosis.

One project will focus on early diagnosis and three will focus on CRPC. The SPORE first received NCI funding in 2001. The researchers’ work has contributed to implementation of clinical trials, FDA approval of a PSA assay, participation in inter-SPORE and Department of Defense national clinical trials, and involvement in national active surveillance initiatives.

The four main projects of this SPORE are: Impact of germline genetic variants on failure of active surveillance for prostate cancer; GR transcriptional activity and the evolution of enzalutamide resistant CRPC; EPHB4 receptor kinase as a target in prostate cancer; and Targeting FOXA1 Downstream Pathways: A novel therapeutic strategy for CRPC.

The University of Pittsburgh SPORE in head and neck cancer contains four projects, which aim to evaluate a chemoprevention strategy using broccoli seed preparations to reduce the morbidity and mortality of head and neck squamous cell carcinoma recurrence and second primary tumor formation, and to develop a safe and effective STAT3 targeting approach that combines systemic delivery for metastatic disease with enhanced delivery to the tumor using a novel microbubble/ultrasound approach.

The SPORE also plans to optimize the therapeutic benefits of cetuximab by combining the antibody with the immunotherapeutic ipilimumab, which targets suppressive regulatory T cells that appear to limit cetuximab-mediated antitumor activity—and to reduce the morbidity and health care costs of over-treating low-risk thyroid nodules and identify differentiated thyroid cancer patients that require aggressive therapy using a novel NGS-based strategy.

Three of the SPORE’s four proposed projects are studying head and neck squamous cell carcinoma, and two projects are dedicated to improving HNSCC treatment using either a novel STAT3 decoy oligonucleotide initially developed in the SPORE program, or an immunotherapy strategy building on promising findings from the current funding period. A new HNSCC project will focus on chemoprevention.

The renewal application now includes a project studying differentiated thyroid cancer, which plans to use a next-generation sequencing approach to improve the sensitivity and specificity of fine needle aspirate biopsies with the goal of reducing unnecessary surgeries for indolent disease.

The Dana-Farber/Harvard Cancer Center kidney cancer SPORE grant explores angiogenesis inhibition, immune modulation, and inhibition of molecular pathways. This SPORE, funded since 2003, is previously responsible for the identification of a gene whose inactivation accounts for approximately one-third of Wilms tumors.

This SPORE includes Beth Israel-Deaconess Medical Center; Dana- Farber Cancer Institute; Harvard Medical School; Harvard School of Public Health; Brigham and Women’s Hospital; Massachusetts General Hospital; and the Children’s Hospital of Boston. The Whitehead Institute at MIT and Georgetown-Lombardi Cancer Center are collaborating institutions.

The SPORE consists of four projects that address strategies for targeting HIF2α, the dominant oncogenic driver of clear-cell RCC; exploring angiogenesis inhibitor resistance mechanisms; and improving the therapeutic index of agents targeting both the mTOR and immune checkpoint pathways.

The projects are supported administrative, biostatistics and tissue acquisition and pathology cores, as well as a career development program and a developmental projects program.

The Mayo Clinic SPORE in ovarian cancer contains four main projects, supported by administrative, biostatistics, biospecimen and animal model cores:

Project 1, Novel Determinants of PARP Inhibitor Sensitivity in Ovarian Cancer, assesses biomarkers of response in both BRCA1/2-mutant and BRCA1/2-wildtype ovarian cancers.

Project 2, Targeting Protein Kinase C-Iota for Ovarian Cancer Therapy, proposes 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 ability of a highly potent and specific PKCι inhibitor to inhibit PKCι signaling in clinical OvCas in vivo through analysis of paired pre- and post-treatment biopsies obtained from ovarian cancer patients enrolled in the expansion cohort of the associated clinical trial.

Project 3, Metformin as a Metabolic Therapeutic in Ovarian Cancer, proposes to elucidate the mechanisms by which metformin affects tumor cell growth and chemoresistance; use patient-derived ovarian cancer xenografts to study pharmacodynamic markers of metformin action; and use serum and tissue samples from a randomized phase II clinical trial of standard therapy to understand the mechanisms of metformin antineoplastic action in the clinical setting.

Project 4, Development of a Th17-Inducing Dendritic Cell Vaccine for Ovarian Cancer, aims to complete a recently opened clinical trial to determine whether FRα-specific Th17 T cell responses can be safely generated in ovarian cancer patients following their adjuvant chemotherapy. This trial will be performed in the setting of minimal residual disease, where immunotherapy might be most effective, according to the SPORE’s abstract.

A breakdown of all funded SPOREs in 2015:

(Source: NCI)

At least half of all funded SPOREs involvemore than one institution and 16 percent involve more than two; 20 percent have multiple PIs. All funded SPOREs currently reside in cancer centers, although that is not a requirement of the program.

According to NCI’s Hecht, the SPORE program is the only NCI grant mechanism that is dedicated entirely to translational research, and requires each scientific project to achieve a human endpoint during the five-year funding period.