Success of two DF/HCC SPOREs prompts renewals
The DF/HCC Lung SPORE, led by Bruce Johnson, MD (DFCI) (left), and the Multiple Myeloma SPORE, led by Kenneth Anderson, MD (DFCI) (right), have each been highly successful in creating cohesion in their respective research programs, sparking new RO1, PO1, and DOD grants, fostering innovative ideas in cancer research, and advancing the careers of junior investigators. As a result, the National Cancer Institute has renewed funding for both SPOREs.
Lung Cancer SPORE
Bruce Johnson, MD (DFCI)
The DF/HCC Lung Cancer SPORE will continue the translation of biological and technological advances into clinically meaningful advances for patients with and at risk for lung cancer. The SPORE consists of five projects:
Genetic analysis of non-small cell lung cancer survival
Co-Leaders: David Christiani, MD, MPH (HSPH), Rebecca Suk Heist, MD, MPH (MGH)
Project one will focus on identifying prognostic and predictive markers of survival in lung cancer. Recent studies by this group has demonstrated the importance of germline polymorphic variants as prognostic and predictive factors, but only a few candidate polymorphisms relative to survival outcomes have been investigated. This project will adopt a high-density pathway approach to more extensively and efficiently explore the role of entire pathways in survival outcomes, specifically selecting pathways with biologic evidence for a role in tumor aggressiveness or treatment response.
Foxa2 and C/EBP transcription factors in the pathogenesis and treatment of lung cancer
Co-Leaders: Daniel G. Tenen, MD (BIDMC), Daniel Costa, MD (BIDMC), Balazs Halmos, MD (Case Western Reserve University)
Project two will further expand studies of transcription factors C/EBPalpha and Foxa2 and move the pathways and potential targets closer to effective clinical applications in malignancies of the airway epithelium. The goal of the studies is to identify novel prognostic markers in early stage non-small cell lung cancer (Foxa2) and the sound introduction of oral compounds—currently in human phase I clinical trials (as is the case of CDDO-Me)—that can re-activate the crucial C/EBP lung differentiation pathway and halt proliferation as well as induce apoptosis in NSCLC.
Targeting erlotinib-resistant lung cancer with rational combination treatments
Project Co-Leaders: Jeffrey Settleman, PhD (MGH), Henning Willers, MD (MGH)
Selective EGFR inhibitors elicit clinical responses in 10-20% of NSCLCs, which correlates with activating EGFR mutations. However, there remains a large fraction of patients for which inhibitors such as erlotinib, as monotherapy, are ineffective. EGFR is expressed in most NSCLCs, suggesting that it may still be an important therapeutic target, in conjunction with additional treatment. Project three will expand the clinical utility of erlotinib by identifying a rational combination with a second treatment to benefit an additional subset of NSCLC patients. These findings should ultimately lead to genotype-driven trials of novel drug combinations or molecularly targeted radiation therapy in patients whose tumors exhibit primary erlotinib resistance.
Translational Studies of Hsp90 Inhibitors in NSCLC
Co-Leaders: Geoffrey Shapiro, MD, PhD (DFCI), Kwok-Kin Wong, MD, PhD (DFCI)
Many proteins that drive lung cancer growth depend on the Hsp90 chaperone, which is required for the stability of multiple oncogenic kinases that drive signaling, proliferation and survival of NSCLCs, including mutant EGFR, Her2, B-Raf, c-Met, and cdk4. Project four will explore compounds that inhibit Hsp90 in preclinical models and clinical trials as potential treatments for lung cancer. Specific inhibitors include geldanamcyins such as 17-AAG, the water-soluble derivatives IPI-504 and pharmacodynamic endpoints and to conduct clinical trials in molecularly defined patient subgroups.
Mechanisms of acquired resistance to epidermal growth factor receptor-targeted agents
Co-Leaders: Pasi Janne, MD, PhD (DFCI), Jeffery Engelman, MD, PhD (MGH)
Most, if not all, patients who initially develop a partial or complete response to gefitinib or erlotinib will eventually develop progression of their cancer while taking these therapies. The only known mechanism of resistance, a secondary mutation in EGFR itself, has been detected in approximately 50% of patients. Using an EGFR T790M in vitro model of resistance previously identified by this project, project five will systematically determine mechanisms of resistance and their in vitro sensitivity to novel therapeutic agents. Tumor specimens will be assessed to determine if these resistance mechanisms can also be detected in patients. Based on these findings, novel therapeutic combinations will be evaluated and serve as the basis for new clinical trials.
Multiple Myeloma SPORE
Kenneth Anderson, MD (DFCI)
The DF/HCC Multiple Myeloma (MM) SPORE represents the integrated efforts of institutions with a unique and long track record of basic and clinical research expertise in MM, joining together to improve patient outcome in MM by more rapidly moving rational novel targeted therapies from the laboratory into clinical protocols. The SPORE consists of six projects:
Proteasome-directed novel myeloma therapies
Leader: Kenneth Anderson, MD (DFCI)
Co-Leader: A. Keith Stewart, MB, ChB (Ontario Cancer Institute)
During the previous funding period, project one translated laboratory findings into the FDA approval of Bortezomib for relapsed refractory and relapsed MM. Although Bortezomib represents a major advance, not all patients respond, those that respond relapse, and no patients are cured.
Project one will focus on using oncogenomics to define mechanisms of Boretezomib resistance. This new paradigm to overcome proteasome inhibitor resistance in MM has great promise not only to change the natural history of this disease, but to serve as a model for targeted therapeutics directed to improve the outcome of patients with other hematologic malignancies as well as solid tumors.
Targeting telomere expansion mechanism in MM
Leader: Nikhil Munshi, MD (DFCI)
Co-Leader: Ronald DePinho, MD (DFCI)
Project two will initiate a phase I study of GRN163L in MM and identify agents that are synergistic with telomerase inhibition in preclinical in vitro and in vivo models. The molecular correlation of response versus resistance identified in the single agent clinical study, coupled with preclinical identification of combinations with synergistic anti-MM activity, will provide the framework for combination clinical trials.
Targeting the Wnt pathway for treatment of MM
Leader: Donald Kufe, MD (DFCI)
Co-Leader: Teru Hideshima, MD, PhD (DFCI)
Project three will target the Wnt/β-catenin pathway as a rational appoach for the treatment of MM. The proposed studies focus on the role of MUC1-C in activating Wnt/β-catenin signaling in MM cells and on the development of agents that disrupt this pathway. The project will also define the involvement of MUC1-C integrating Wnt/β-catenin signaling with activation of the IKKβ->NF-κB pathway and Hsp90-dependent targeting of MUC1-C to mitochondria for the development of rationally based combinations. Agents that target the Wnt/β-catenin pathway will be studied alone and in combination for effects on myeloma cell growth and survival in the bone marrow microenvironment and in xenograft models. The results of these studies will be used to design clinical trials of Wnt/β-catenin inhibitors alone and in combination for the treatment of patients with refractory MM.
Targeting activation of NFκB pathways in MM
Leader: P. Leif Bergsagel, MD (Mayo Clinic)
Co-Leader: Dharminder Chauhan, JD, PhD (DFCI)
Half of MM patients have hyperdiploidy and the other half have one of five recurrent immunoglobulin gene translocations. In both cases these are felt to represent primary genetic events, with the consequence of dysregulation of the expression of a cyclin D gene. Subsequent tumor progression occurs with activating mutations of RAS, a promiscuous array of mutations that activate the non-canonical NFκB pathway. The hypothesis for project four is that in the majority of MM patients the NFκB is activated as a result of ligand-dependant interaction in the bone marrow microenvironment, and only ~20% of patients acquire mutations causing constitutive activation.
The proposed studies will dissect out the mechanisms causing activation of the canonical and non-canonical NFκB pathway and explore the functional consequence of specific targeted inhibition using small molecule inhibitors in relevant pre-clinical models. The results of these studies will be to introduce into clinical trials promising targeted NFκB pathway inhibitors.
Molecular markers of plasma cell neoplasm evolution
Leader: Rafael Fonseca, MD (Mayo Clinic)
Co-Leader: S. Vincent Rajkumar, MD (Mayo Clinic)
By performing in situ single cell analysis on previously collected slides and samples from a reference cohort of patients, and utilizing our expertise using the oligo based array comparative genomic hybridization (aCGH), project five will continue the search for markers causative and predictive of progression from monoclonal gammopathy of unknown significance (MGUS) to MM.
Identifying high-risk genotypes for MM: a collaborative multi-ethnic case-control study
Leader: Wendy Cozen, DO, MPH (Univ. of Southern California)
Co-Leader: David Conti, PhD (Univ. of Southern California)
Prior SPORE studies have found evidence linking polymorphisms in genes that control two important plasma cell growth factors, interleukin (IL)-6 and insulin-like growth factor (IGF)-1, with susceptibility to MM. In addition, there are positive associations between polymorphisms of certain DNA repair genes and MM risk. These studies had strong prior hypothesis but small sample sizes and disproportionably affects African-Americans and to a lesser degree, Hispanics. Project six will confirm these findings in a large multi-ethnic sample of 559 cases and 885 controls from five separate studies with existing DNA samples. This project will ultimately contribute to the understanding of the genetic susceptibility to MM needed for the development of both treatment and prevention strategies.