Yale SPORE in Skin Cancer
Yale University
Principal Investigator(s):
Marcus Bosenberg, MD, PhD
Harriet Kluger, MD
- Principal Investigator(s) Contact Information
- Overview
- Project 1: Harnessing Epigenetic Regulation of Endogenous Retroelements in Melanoma
- Project 2: Overcoming Melanoma Treatment Resistance with Cytokine Immunotherapy
- Administrative Core
- Biospecimen Core
- Biostatistics and Bioinformatics Core
- Developmental Research Program (DRP)
- Career Enhancement Program (CEP)
Principal Investigator(s) Contact Information
Marcus Bosenberg, MD, PhD
Anthony N. Brady Professor of Dermatology, Pathology, and Immunobiology
Director, Yale Center for Immune-Oncology
Co-Leader, Cancer Immunology Program, Yale Cancer Center
Yale University
15 York Street, LMP 5036
New Haven, Connecticut, 06520
203-785-4094
Harriet Kluger, MD
Harvey and Kate Cushing Professor of Medicine (Oncology) and of Dermatology
Vice Chair for Translational Research, Internal Medicine; Chief, Division
Yale University
333 Cedar Street, WWW 211B
PO Box 208032
New Haven, Connecticut, 06520
203-785-2351
Overview
The Yale SPORE in Skin Cancer (YSPORE) goal is to decrease mortality from melanoma by developing novel drugs and regimens to treat patients once it metastasizes and develop predictive biomarkers to select patients for the optimal treatment regimen. YSPORE leans on the immense scientific and clinical strengths at Yale School of Medicine and Yale Cancer Center including immunobiology, genetics, epigenetics, quantitative sciences, immuno-oncology, animal models, and digital pathology. Advances in systemic therapies for advanced melanoma, immune therapies that prolong survival, pose a new set of challenges for clinicians which will be addressed by the proposed research program, as we strive to increase the long-term survival for all melanoma patients.
Specific Aims:
Aim 1: Study novel drugs that target the epigenetic modifier KDM5B, to upregulate endogenous retroelements and enhance T cell infiltration in tumors that are unresponsive or poorly responsive to immune checkpoint inhibitors.
Aim 2: Study novel cytokines to overcome resistance to immune checkpoint inhibitors in patients whose melanoma has progressed on anti-PD-1.
Aim 3: Develop new research directions to decrease mortality from melanoma and nurture the next generation of translational investigators focusing on skin cancer through a Developmental Research Program and a Career Enhancement Program.
Project 1: Harnessing Epigenetic Regulation of Endogenous Retroelements in Melanoma
Project Co-Leaders:
Qin Yan, PhD (Basic Co-leader)
Marcus Bosenberg, MD, PhD (Applied Co-leader)
Despite remarkable progress in treating advanced melanoma, prognosis remains variable. Specifically, nearly all metastatic melanoma patients develop resistance to targeted therapy with time, while approximately half do not respond to immunotherapy. These challenges highlight an urgent need to develop novel therapeutic interventions, improve current treatments, and develop biomarkers that predict response. Emerging evidence suggests that epigenetic regulators KDM5B and SETDB1 are therapeutic targets and endogenous retroelements (REs) may serve as biomarkers of response to immunotherapies. Our long-term goal is to translate our findings of novel mechanisms involved in melanoma progression to the clinic. The objectives of this project are to dissect the cellular mechanisms by which KDM5B and SETDB1 loss induce anti-melanoma immunity, develop biomarkers to predict response to immune checkpoint inhibitors, and to evaluate the therapeutic potential of depleting KDM5B in melanoma. Our central hypotheses are that KDM5B and SETDB1 targeting de-repress the expression of retroelements to initiate robust anti-melanoma immune responses, and retroelements can be harnessed to predict response to immunotherapy. The hypothesis is supported by previous studies as well as our own preliminary data from patient-derived melanomas and preclinical melanoma models. The rationale is that better understanding of how KDM5B and SETDB1 suppress melanoma growth and anti-tumor immune responses will result in new and innovative approaches to treat melanoma. The proposed research is conceptually, technically, and clinically innovative, because it aims to examine the therapeutic potential of KDM5B depletion using “first in class” KDM5B degraders, and to evaluate retroelement levels as novel predictive biomarker for response to immunotherapy. The results from these studies could impact the treatment of patients with melanoma and increase our understanding of the factors that regulate anti-tumor immune responses.
Specific Aims:
Aim 1: Dissect the mechanisms of immune responses induced by KDM5B and SETDB1 loss.
Aim 2: Evaluate the therapeutic potential of depleting KDM5B in melanoma.
Aim 3: Evaluate retroelements suppressed by KDM5B and SETDB1 as predictive biomarkers in human melanoma.
Project 2: Overcoming Melanoma Treatment Resistance with Cytokine Immunotherapy
Project Co-Leaders:
Harriet Kluger, MD (Clinical Co-leader)
Aaron Ring, MD, PhD (Basic Co-leader)
Major changes have occurred in treatment of unresectable melanoma in the last decade, unfortunately, almost half the melanoma patients do not respond to immune checkpoint inhibitors (ICI) upfront, and others develop recurrent or resistant disease over time. Immunotherapies that can stimulate immunity in ICI-resistant melanoma are still therefore urgently needed. Cytokines have potent immunostimulatory activities that make them attractive candidates for use in combination with ICIs, and Interleukin 18 (IL-18) is particularly appealing, because the IL-18 receptor is specifically upregulated in CD8 tumor infiltrating lymphocytes and is widely expressed on natural killer (NK) cells. However, clinical trials of recombinant IL-18 were unsuccessful, likely due to upregulation of the endogenous IL-18 receptor antagonist or IL-18 binding protein, IL-18BP, which inhibits the immunostimulatory effects of IL-18. A clinical grade “decoy resistant” IL-18 (DR18) has been developed and licensed to Simcha Therapeutics by Yale University (ST-067). ST-067 is currently being investigated in a first-in-human clinical trial as monotherapy. In pre-clinical models, DR18 synergizes with anti-PD-1. Furthermore, in murine models, DR-18 is highly effective in treating ICI-resistant MHC class I deficient tumors, consistent with the ability of IL-18 to also activate NK cells. We hypothesize that combining DR-18 with immune checkpoint inhibitors can overcome ICI resistance in melanoma via activation of NK cells, T effector cells and stem-like memory T cells.
Specific Aims:
Aim 1: We propose to conduct a series of pre-clinical studies utilizing novel animal models developed in house with clinically relevant melanoma mutations to determine the mechanism of response and resistance of the combination of DR-18 with clinically approved ICIs (inhibitors of PD-1, CTLA-4 and LAG-3).
Aim 2: We will conduct a phase I/II clinical trial of ST-067 with immune checkpoint inhibitors in patients whose disease has progressed on a prior regimen containing anti-PD-1.
If successful, these studies will support further development of ST-067 with ICIs in patient subsets carefully defined by immune cell characteristics. This approach can be applied to patients with other types of anti-PD-1 resistant tumors as well.
Administrative Core
Core Co-Directors:
Marcus Bosenberg, MD, PhD
Harriet Kluger, MD
Mario Sznol, MD
The Administrative Core (Core A) is critical to the success of the Yale SPORE in Skin Cancer (YSPORE). The primary purpose of the Core is to support and facilitate transdisciplinary research efforts in skin cancer and identify new challenges and opportunities as they emerge. The Administrative Core serves as the central coordination point for YSPORE investigators, with responsibility for monitoring the progress of all projects and cores toward a translational/clinical endpoint. These services include provision of (a) fiscal management, (b) clerical and organizational support, (c) mechanisms for internal and external review, (d) support for enhancement of scientific interactions and collaborations among the Project/Core leaders, (e) mechanisms to monitor projects and cores for scientific progress, (f) coordination of outreach efforts, and (g) mechanisms to expand research in skin cancer beyond the activities of the SPORE, both within Yale and outside of Yale. Core A will organize joint scientific research in progress meetings held with the SPORE researchers, the annual inter-SPORE workshops in collaboration with Administrative Cores at other sites and the annual meetings with the Internal and External Advisory Boards.
Biospecimen Core
Core Co-Directors:
Ruth Halaban, PhD
Marcus Bosenberg, MD, PhD
Harriet Kluger, MD
The Biospecimen Core (Core B) is the cornerstone of all Yale SPORE in Skin Cancer (YSPORE) activities. It addresses the broad melanoma patient specimen needs of all the projects that are not met by current shared facilities at Yale. In addition to collecting, storing, and distributing a wide range of specimens and reagents, the core performs quality assurance testing and a wide range of molecular analyses of specimens. The core interacts extensively with investigators in each project, the Bioinformatics and Biostatistics Core, the Clinical Trial Office, and Yale Cancer Center shared resource cores such as Yale Pathology Tissue Services and Yale Center for Genome Analysis. The services of the Biospecimen Resource Core enhance the efficient operation of the translational studies by YSPORE investigators in a cost-effective manner and expedite the application of discoveries from the bench to clinical practice, and clinical results to basic research.
Biostatistics and Bioinformatics Core
Core Co-Directors:
Shuangge Ma, PhD
Yuval Kluger, PhD
The goals of the Biostatistics and Bioinformatics Core are to address the study design and analysis needs of the Yale SPORE in Skin Cancer projects, the Developmental Research Program (DRP), and the Career Enhancement Program (CEP), and to address the analytical and data management needs of the Biospecimen Core. Drs. Kluger and Ma will continue to serve as Co-Directors of this Core and will be assisted by statisticians and bioinformaticians with unique expertise and extensive experience. The Specific Aims of the Biostatistics and Bioinformatics Core are as follows.
Specific Aims:
Aim 1: Provide optimal biostatistical and bioinformatics support to all SPORE projects and investigators.
Aim 2: Provide effective data management for all the SPORE projects.
Aim 3: Develop innovative biostatistics and bioinformatics methods.
Aim 4: Promote program-specific research opportunities involving biostatistics and bioinformatics trainees and faculty.
Developmental Research Program (DRP)
Program Director:
David Stern, PhD
The primary goal of the Yale SPORE in Skin Cancer Developmental Research Program (DRP) is to provide limited support (maximum of $50,000/year, typically for no more than two years) for a broad spectrum of innovative skin cancer pilot projects (involving research, resources, and technology development applicable to human skin cancer risk, prevention, diagnosis, prognosis, or treatment). These pilot projects must have promising translational research potential, with anticipation that they can eventually develop into, or be incorporated into, full projects with an unequivocal clinical translational component. Such projects could either be developed into independent external funding at a scope and scale equivalent to a NIH R01 grant, or alternatively augment or replace a Project in future cycles of the Yale SPORE in Skin Cancer. A second goal of this DRP is broaden the collective of Yale investigators who are actively engaged in research related to human cutaneous oncology.
Career Enhancement Program (CEP)
Program Director:
David Stern, PhD
The Career Enhancement Program (CEP) of the Yale SPORE in Skin Cancer will develop a new cadre of investigative cutaneous oncologists and scientists committed to multidisciplinary studies investigating the relevance of biological discoveries in human skin cancer risk, prevention, diagnosis, prognosis or treatment, and enhance the careers of individuals who are already productively investigating this field. CEP is able to support of 2-3 faculty-level awards per year using institutional matching funds. Potential candidates for these awards include promising junior faculty who are either appointed at Yale or are outside candidates or new recruits for Yale appointment. Alternatively, candidates may be established investigators, either currently at Yale or in the process of being recruited to Yale, with previous research focus in other arenas, but who will re-channel a significant portion of their focus to translational research in cutaneous oncology. All junior faculty awardees are paired with an established investigator in translational cutaneous oncology with a documented record of successful mentoring.