Dana-Farber/Harvard Cancer Center SPORE in Multiple Myeloma

Dana-Farber Cancer Institute

Principal Investigator(s):

Kenneth Anderson, MD

Nikhil Munshi, MD

• Principal Investigator(s) Contact Information
• Overview
• Project 1: Therapeutically Targeting Ubiquitin Receptors in Multiple Myeloma
• Project 2: Targeting AP Nuclease, a Mediator of Genomic Instability in MM
• Project 3: Targeting mutated MYD88 signaling in WM
• Administrative Core
• Tissue Banking Core
• Pathology and Biospecimen Core
• Biostatistics and Bioinformatics Core
• Developmental Research Program
• Career Enhancement Program

Principal Investigator(s) Contact Information

Kenneth Anderson, MD
Kraft Family Professor of Medicine, Harvard Medical School
Director, Jerome Lipper Multiple Myeloma Center
Dana-Farber Cancer Institute
Department of Medical Oncology
450 Brookline Avenue
Boston, MA 02115-5450
(617) 632-2144

Nikhil Munshi, MD
Professor of Medicine, Harvard Medical School
Kraft Family Chair
Dana-Farber Cancer Institute
Department of Medical Oncology
450 Brookline Avenue
Boston, MA 02115-5450
(617) 632-5607

Overview

The Dana Farber/Harvard Cancer Center (DF/HCC) multiple myeloma (MM) SPORE application consists of 3 Research Projects and 3 Cores, as well as the Career Enhancement and Developmental Research Programs. During the previous funding period, we have capitalized on the complementary strengths of the research, clinical expertise, and facilities of the Harvard affiliated institutions. We have successfully translated multiple novel agents from the bench to the bedside and FDA approval for treatment of MM. In this SPORE renewal application one new project has evolved from prior Developmental Projects, and three investigators who are now Co-PI’s have previously received Developmental Research or Career Enhancement Awards. This new project focuses on developing novel therapeutic strategies in Waldenstrom’s macroglobulinemia (WM), a plasma cell disorder with unique biology. The group as a whole has a long-term commitment to translational MM research, with the necessary administrative, basic science, and clinical infrastructure. The spectrum of diseases evaluated spans from MGUS to plasma cell leukemia to WM. This large combined patient base assures rapid accrual and evaluation of the therapeutic efficacy of novel agents identified in this program with over 40 active protocols. Success of both the preclinical and clinical components of this Program is dependent upon synergy and communication between these investigators which is assured by the joint research efforts. Currently there is systematic quality-controlled exchange of samples for correlative basic laboratory studies. The overall goal of this DF/HCC myeloma SPORE is to take advantage of our understanding of the genetic and molecular basis of MM and WM to develop novel, effective therapeutic strategies. The translational nature of the SPORE is highlighted by the fact that most of our projects have emanated from clinical studies from the outset. Specific Projects are: (1) Therapeutically Targeting Ubiquitin Receptors in MM; (2) Targeting AP Nuclease, a Mediator of Genomic Instability in MM; (3) Targeting Mutated MYD88 Signaling in WM; An Administration Communication and Planning; Tissue banking and Biostatistics and Bioinformatics Cores, will continue to support the program. This Program therefore helps move rational novel targeted therapies from the laboratory to clinical protocols to improve patient outcome in MM.

Project 1: Therapeutically Targeting Ubiquitin Receptors in Multiple Myeloma

Project Co-Leaders:
Kenneth C. Anderson, MD (Clinical Co-Leader)
Dharminder Chauhan, PhD (Basic Science Co-Leader)

The ubiquitin proteasome system (UPS) regulates a non-lysosomal intracellular protein degradation pathway that is required for normal protein homeostasis. Dysfunction of the UPS is associated with pathogenesis of various human diseases including multiple myeloma (MM); therefore, inhibitors of UPS pathways offer great promise as a novel therapeutic strategy. We have characterized targeting of UPS in MM using our in vitro and in vivo models of the MM cell in the bone marrow (BM) milieu, specifically delineating the molecular and cellular mechanisms whereby proteasome inhibitors (PI) target tumor cells and its interactions with the BM microenvironment. These preclinical studies and clinical trials provided the basis for FDA approval of PI in MM. Even though PI are major advances, they are associated with possible off-target toxicities and the eventual development of drug-resistance. Therefore, our recent studies have focused on targeting enzymes modulating protein ubiquitin-conjugation and -deconjugation rather than the proteasome itself, with the goal of generating more specific and less toxic anti-tumor agents. Previously we reported on targeting deubiquitylating enzymes USP14/UCHL5 and our most recent efforts have focused on targeting another major component of UPS, Ubiquitin Receptors (UbRs). Our Preliminary Studies show that UbR Rpn13/ADRM1 is highly expressed in MM cells than in normal plasma cells, and that inhibiting Rpn13 triggers MM cell growth inhibition, even in PI-resistant MM. The current proposal aims to investigate the hypothesis that inhibition of the UPS at the level of UbRs, upstream of the proteasome, can inhibit MM cell growth and overcome PI resistance. To achieve these goals, following Specific Aims will be pursued: 1: Functional characterization of Ubiquitin Receptors in MM pathogenesis. 2: To design specific UbR inhibitors and/or degraders, and assess their in vitro specificity and mechanism of action, either alone or in scientifically-informed combinations; 3: To pre-clinically evaluate in vivo anti-MM activity of novel UbR inhibitors and/or degraders, either alone or in combination for translation into clinical trials. This new paradigm to target UPS pathways in MM at the level of UbRs has great clinical promise and may also serve as a model for targeted therapeutics in other cancers.

Project 2: Targeting AP Nuclease, a Mediator of Genomic Instability in MM

Project Co-Leaders:
Nikhil C. Munshi, MD (Clinical Co-Leader)
Masood A. Shammas, PhD (Basic Science Co-Leader)

A prominent feature of multiple myeloma (MM) and other malignancies is significant genomic instability leading to clonal evolution and disease progression. We previously reported that homologous recombination (HR), the error free DNA repair system in normal cellular environment, is dysregulated in MM as well as esophageal cancer, and contributes to genomic instability, development of drug resistance, and tumor growth. In the previous funding period, we observed significantly elevated nuclease activity in newly-diagnosed and relapsed MM compared to MGUS patient samples. A functional siRNA screen identified that two members of apurinic/apyrimidinic (AP) nuclease activity (APEX 1 and 2) are amongst the most prominent contributors to dysregulated nucleolytic and HR activities. We also observed that the high expression of APEX1 and APEX2 correlated with increased copy number events and poor survival in MM. In our preliminary studies we observe that transgenic and chemical inhibition of AP nuclease activity inhibited DNA breaks, HR activity, and genomic instability in MM cells, as well as induced a strong G2/M arrest; while transgenic upregulation of AP activity increased DNA breaks, HR activity, genomic instability, and led to oncogenic transformation in normal human cells as well as tumorigenesis in zebrafish and mouse models. We, therefore, hypothesize that elevated AP expression drives genomic instability and clonal evolution, and may represent a potential therapeutic target. To investigate the role of APEX nucleases in MM and to evaluate their therapeutic potential, we will To investigate the role of APEX nucleases (APEX1 and 2) in genomic evolution in MM (Sp. Aim 1); investigate APEX1/APEX2-induced genomic instability and malignant transformation in a transgenic mouse model of B cell malignancy (Aim 2); and evaluate inhibitors of AP nuclease activity in MM (Aim 3) alone and in combination with other anti-MM agents in vitro, in vivo and in Phase I/II clinical study in relapsed refractory multiple myeloma. This project will help identify novel target as well as drugs that may help inhibit tumor growth, prevent/delay genomic evolution, which in turn may help make MM cells genomically stable.

Project 3: Targeting mutated MYD88 signaling in WM

Project Co-Leaders:
Steven P. Treon, MD (Clinical Co-Leader)
Nathanael S. Gray, PhD (Basic Science Co-Leader)

By whole genome sequencing, we discovered highly recurring MYD88 mutations in 95-97% of Waldenstrom’s macroglobulinemia (WM) patients that promote constitutive pro-survival NF-kB activation through IRAK1/IRAK4 and BTK. These findings enabled us to perform a pivotal clinical trial that led to the approval of the BTK inhibitor ibrutinib for WM. Despite high response rates, most responses to ibrutinib are partial, and persistent IRAK1/IRAK4 signaling appears responsible for this intrinsic resistance to ibrutinib. We therefore propose to create inducible knockdown mutants of IRAK1, IRAK4 and both in MYD88 mutated WM cell lines to clarify their importance in mediating pro-survival signaling. We will also perform replacement experiments by transduction of kinase intact or kinase dead IRAK1 and IRAK4 to clarify the importance of scaffold versus kinase mediated pro-survival signaling. The findings from these experiments will guide development of highly selective and potent prototype inhibitors of IRAK1 (JH-X- 119-01) and IRAK1/IRAK4 (JH-I-25) that we have manufactured, to be evaluated as a single agent and in combination with ibrutinib in WM. Acquired resistance to ibrutinib is also an emerging problem in WM patients. We recently identified BTKCys481 mutations that abrogate ibrutinib-BTK binding in samples from half of WM patients who progressed on ibrutinib, and showed that transduction of the most common BTK mutation (BTKCys481Ser) led to activation of ERK1/2 survival signaling, inflammatory cytokine production, and ibrutinib resistance in MYD88 mutated WM cells. In recent work, we identified HCK, a SRC family member that is down-regulated at later stages of B-cell ontogeny, as an important component of mutated MYD88 survival signaling that activates BTK, as well as AKT and ERK1/2. We propose to delineate the importance of HCK blockade to overcoming acquired ibrutinib resistance. In this aim, we have developed highly potent and selective prototype HCK kinase inhibitors from two distinct scaffolds (SB1-G-33 and A419259) that show potent cytotoxic, HCK and BTK inhibition in BTKCys481 mutated WM cells. We propose to optimize these molecules suitable for human studies. We will validate the lead IRAK and HCK inhibitors developed in these studies using our in vivo WM rodent models for translation to clinical trials.

Administrative Core

Core Directors:
Kenneth C. Anderson, MD (Co-Director)
Nikhil C. Munshi, MD (Co-Director)

The purpose of the Administration, Communication, and Planning Core is to assure the coordination of the Dana Farber/Harvard Cancer Center (DF/HCC) Myeloma SPORE components and to provide oversight and leadership of the scientific, administrative, and fiscal aspects of the SPORE. The SPORE Directors will oversee the administrative coordination of the various clinical and laboratory studies outlined in this Program. They will integrate scientific and clinical efforts within and between Projects, and assure the translation of laboratory findings to the bedside; and conversely, the initiation of laboratory studies stemming from clinical observations. During the prior funding period, the infrastructure has been created to have seamless communication and exchange of data between SPORE sites, facilitating collaborative preclinical studies and clinical trials. Multiple joint publications, completed and ongoing clinical trials, and the translation of several novel targeted therapies from bench to bedside confirm the communication and integration of our efforts. This Core will continue to facilitate exchange of information among the SPORE members, as well as the internal and external advisory committees. It will provide clinical research nursing support for the proposed clinical trials. In addition, as in the previous funding period, a clinical study coordinator will assure appropriate sample acquisition and trafficking. The grants administrator will allocate resources in a timely and integrated fashion to facilitate successful completion of the proposed studies.

Tissue Banking Core

Core Directors:
Nikhil C. Munshi, MD (Co-Director)
Herve Avet-Loiseau, MD (Co-Director)

The goals of the Tissue Bank Core are to aid SPORE investigators: 1) to identify tumor biologic and molecular genetic correlates of diagnosis, prognosis, response, progression, and survival in the context of the SPORE related investigations; 2) to maintain a searchable database of clinical and laboratory data for use by SPORE investigators; and 3) to provide a resource of banked specimens for future studies. Core Laboratory functions are designed to increase the power of the individual projects to detect biologic differences among patients entering the SPORE studies, to identify molecular correlates of response versus resistance, and to be flexible enough to address individual investigator needs. In the previous funding period, the tissue core received, processed, stored, archived and distributed clinically-annotated cellular (bone marrow and PB cells), molecular (DNA and RNA), and serum samples to investigators participating in this SPORE. Samples from the SPORE have been collected, tested, and archived in addition from other Core resources, such as the DF/HCC and Program Project reference laboratories; however, these resources are being shared between this core resource, thereby increasing the pool of samples available for correlative science by the SPORE investigators. In this renewal application we will continue to collaborate with the Intergroupe Francophone du Myeloma (IFM) in sharing archived and future samples. IFM has over 13,000 clinically annotated samples with long follow ups. During last 6 years we have shared samples between our groups and generated number of joint publications. We have also incorporated the Waldenstrom’s macroglobulinemia samples in this core. This Core provides an independent, current, and quickly searchable database of clinical and laboratory results and archived biospecimens. All patients have measurement of key biological variables requested by SPORE investigators. Unused specimen including sorted cells, DNA, RNA, and cytospin slides are stored for future use on all patients. Subsequent use of banked samples beyond that specified in this SPORE proposal will be provided only with agreement from the SPORE Director and the SPORE Principal Investigators, after approval from the SPORE Tissue Use Committee.

Biostatistics and Bioinformatics Core

Core Directors:
Giovanni L. Parmigiani, PhD (Co-Director)
Mehmet K. Samur, PhD (Co-Director)

The purpose of the Biostatistics and Bioinformatics Shared Resource Core 2 is to provide consultation and collaboration on quantitative methods on all SPORE Projects, Developmental Projects, and Admin Core and Shared Resource Core 1. Successful collaboration between the project leaders and the biostatisticians and computational biologists in this SPORE, as well as members of the other Cores, is essential to achieve the goals of the projects. Members of this core will provide support for the design, analysis, and reporting of laboratory, animal, translational, genomic, and clinical studies. Depending on the project, these collaborations could range from short consultations to large collaborative projects and will include assistance in preparation of grant applications and manuscripts related to the SPORE projects. The Core members will also provide statistical and bioinformatics mentoring to the researchers, with a particular emphasis on Career Development Awardees and Developmental Project Investigators. Important for the success of the SPORE is the coordination of data management and quality control procedures. The biostatisticians and computational biologists are an integral part of this process at the DFCI and will continue to provide input on the existing procedures, as well as recommendations on additional computational infrastructure, which might be necessary for this SPORE.

Developmental Research Program

Program Directors:
Kenneth C. Anderson, MD (Co-Director)
Nikhil C. Munshi, MD (Co-Director)

The objectives of the Developmental Research Program are to provide a continuous flow of new ideas and projects to stimulate myeloma research in the context of the Myeloma SPORE. It encourages new research directions and methodologies and facilitates collaborations. By providing initial support to pilot projects, it will foster the development of new translational projects. It also allows the Myeloma SPORE to have participation and recruitment of investigators from all the DF/HCC institutions as well as all our collaborators, such as Jonathan Licht, MD, a Developmental Project Award recipient from the Lurie Northwestern Cancer Center who was a PI in the previous SPORE; and Stephane Minvielle, PhD, from Nantes France who was Development Project Award recipient and has contributed to our SPORE tissue bank. This Program will rely on scientific and programmatic review by the SPORE Governance Committee, which will assure selection of the most promising, highest quality, projects with high likelihood of translational impact. Specifically, the SPORE Governance Committee will be responsible to:

1. Solicit applications and/or identify novel myeloma research projects,
2. Evaluate these projects for funding,
3. Fund the most innovative Developmental Projects,
4. Re-evaluate projects for possible transition into full project status, and
5. Evaluate success of the program.

Career Enhancement Program

Program Directors:
Kenneth C. Anderson, MD (Co-Director)
Nikhil C. Munshi, MD (Co-Director)

The investigators assembled in the DF/HCC Myeloma SPORE have a substantial long-term record in mentorship and development of junior faculty working in translational myeloma research. The goal of the Career Enhancement Program of our Myeloma SPORE is to build upon this record and establish a formal process for the identification, selection, funding, and mentoring of individuals pursuing careers in the study of the basic and clinical aspects of myeloma.

These awards will facilitate the development of physicians, physician scientists, clinical investigators, epidemiologists, and scientists in training within the Myeloma SPORE Program towards faculty status. Thus, candidates will be junior faculty or fellows and postdoctoral fellows within the various training programs across DF/HCC and participating institutions. We will also allow established investigators who wish to develop or refocus their careers on translational cancer research in myeloma to apply for this award. It is our goal to attract, mentor, and assure the success of multiple candidates within the timeframe of this SPORE. Success is defined as the development of physician/scientists in training towards careers as independent investigators.

The Career Enhancement Program (CEP) of the DF/HCC Myeloma SPORE has been very successful at developing the next generation of translational researchers in myeloma over the last fifteen years. It will continue to accomplish this goal by the following aims:

1. To solicit applications for Career Enhancement Awards
2. To evaluate applications to select Career Enhancement Award recipients
3. To mentor recipients of CEP Awards
4. To evaluate the CEP Program and its success on an ongoing basis

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