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Twenty-six new members join DF/HCC

Twenty-six individuals have recently joined DF/HCC. See below to learn more about these scientists and their research interests.

 

Philippe Armand, MD, PhD (DFCI)
Lymphoma and Myeloma Program

Research focus: inhibitors of the mammalian target of rapamycin (mTOR) kinase have shown clinical activity in several lymphoma subtypes. Sirolimus, an mTOR inhibitor, is also active in the treatment and prophylaxis of graft-versus-host disease (GVHD) after allogeneic hematopoietic stem-cell transplantation (HSCT). The lab hypothesized that the use of sirolimus for GVHD prophylaxis in patients with lymphoma might lead to improved survival after transplantation through a decreased incidence of disease progression. The lab analyzed 190 patients who underwent transplantation for lymphoma and compared the outcomes of patients who received sirolimus for GVHD prophylaxis with those of patients who received transplantation with a combination of a calcineurin inhibitor and methotrexate without sirolimus. Overall survival (OS) after transplantation was significantly superior in the sirolimus group. No such survival advantage was apparent in a similar comparison of patients who underwent transplantation for diseases other than lymphoma. This study suggests that sirolimus can independently decrease the risk of lymphoma progression after RIC HSCT, paving the way for prospective clinical trials.

Donna Berry, PhD (DFCI)
Prostate Cancer Program

Research focus: improving patient/clinician communication via electronic self-report assessment for cancer (ESRA-C). Assessment of common cancer symptoms and quality of life (QOL) during therapy, notably psychosocial concerns, is known to be incomplete at times. Electronic self-report methods for patients are now available, yet evidence that such methods improve patient/clinician communication is lacking. A confidential, electronic self-report method for patients to report symptoms and concerns, ESRA-C, has been created, and the lab reports on a randomized clinical trial (RCT) of its effectiveness.

Michael Birrer, MD (MGH) 
Gynecologic Cancer Program

Research focus: characterizing the molecular biology of gynecologic cancers. The lab has identified the genetic alterations of specific oncogenes and tumor suppressor genes in cervical, endometrial, and ovarian cancers and correlated these results with the clinical behavior of these cancers. In 2000, the lab was awarded one of the Director’s Challenge Grants for the genomic analysis of ovarian cancer via a large-scale study of expression profiling of ovarian cancer in collaboration with MDACC, MSKCC, and University of Penn. This effort has resulted in the characterization of the whole genome gene expression profile of ovarian tumors of different histology and grade.

Jorge Chavarro, MD, SM, ScD (BWH)
Cancer Epidemiology Program; Prostate Cancer Program

Research focus: investigating the role of diet and the interaction between dietary and genetic factors in the pathogenesis of diseases affecting reproductive and hormone sensitive organs, particularly malignancies of reproductive organs. This broad interest is currently focused in two areas. First, investigating the role of fatty acids and their metabolism in the development and progression of prostate cancer. Using data from ongoing cohort studies, the lab studies the relationships of dietary fatty acid intakes and biomarkers of fatty acid intake and their metabolism, including de novo lipogenesis, with prostate cancer risk and survival. Also, because prostate cancer treatment often has adverse cardiovascular and metabolic consequences, the lab is investigating the role of modifiable lifestyle factors on non-cancer mortally, particularly cardiovascular disease, among men with prostate cancer. In addition to the prostate cancer work, the team is currently investigating how different dietary and lifestyle factors are related to male and female fertility and infertility treatment outcomes with the goal of identifying strategies for fertility preservation in cancer survivors and in the general population.

Aileen Chen, MD, MPP (HMS)
Lung Cancer Program; Outcomes Research Program

Research focus: developing and evaluating new technologies for lung cancer treatment, including IMRT, respiratory management techniques, and imaging technologies. The lab is also interested in population-based research in patients with thoracic cancers and is working on projects on technology adoption, access to care, and patient outcomes.

Rachael Clark, MD, PhD (BWH)
Cancer Immunology Program; Cutaneous Oncology and Melanoma Program

Research focus: developing novel therapies for squamous cell carcinomas and their premalignant precursor lesions that are safe for use in normal and immunosuppressed individuals. The skin is an accessible tissue in which to study tumor immunity because immune reactions in the skin are visible, easily sampled and can be manipulated with topical medications. Because impaired T cell homing and recruitment of regulatory T cells occur in many human malignancies, findings and novel therapies arising from this work should be applicable to the treatment of other types of human cancer.

Corey Cutler, MDCM, MPH (DFCI)
Cancer Immunology Program; Leukemia Program

Research focus: prevention and treatment of acute and chronic graft-versus-host disease (GVHD) including development of several new strategies to prevent acute GVHD using the novel compound, sirolimus. As a result of investigations, one strategy is now the subject of a randomized phase III trial being conducted by the Bone Marrow Transplant Clinical Trials Network with Cutler as principal investigator. Another focus is the prevention and treatment of chronic GHVD for which there are currently no proven pharmacologic methods for preventing. The lab has begun a clinical trial to study the monoclonal B cell antibody, rituximab, to assess its possible role in the prevention of chronic GVHD. The lab is also investigating several other novel compounds and approaches for the treatment of established and steroid resistant chronic GVHD. A secondary focus of the research is outcomes analysis and decision making in stem cell transplantation.

Dan Duda, DMD, PhD (MGH) 
Angiogenesis, Invasion, and Metastasis Program

Research focus: adult stem cell biology and the role it plays in tumor angiogenesis, growth, and metastasis. The long-term goal is to gain fundamental insight into solid tumor cellular biology and to directly translate this knowledge into improved therapies by conducting correlative studies in clinical trials in cancer patients.

Leena Gandhi, MD, PhD (DFCI) 
Lung Cancer Program

Research focus: lung cancer metastasis with the goal to translate basic research findings and to conduct correlative scientific studies in conjunction with early phase clinical trials. The focus has been primarily on small cell lung cancer; additionally, the focus is on preclinical and clinical studies of anti-angiogenic and anti-metastatic agents with the goal of defining new therapeutic targets in this disease. Recently, the lab has developed measurements of MMPs into a multiplex assay of angiogenic biomarkers in blood and urine to be used in correlative studies with trials of anti-angiogenic agents.

 

Jason Gold, MD (BWH) 
Cancer Immunology Program; Gastrointestinal Malignancies Program

Research focus: the role of inflammation in the development and growth of gastrointestinal tumors. It has long been thought that inflammation is involved in the development of gastrointestinal cancers though the method by which inflammation initiates and promotes tumor growth is not known. Recently a pathway consisting of specially polarized CD4+ helper T cells and associated cytokines has been found to be critical in autoimmune and chronic inflammatory conditions. It has been postulated that this pathway, called the T helper 17 or Th17 pathway, may be involved in cancer; to date this has not been studied well. The lab hypothesizes that Th17-polarized CD4+ T cells and their associated inflammatory cytokines are involved in the development and growth of gastric and colorectal cancer. A better understanding of the role of inflammation in the development and growth of gastrointestinal tumors may help reveal novel targets for the chemoprevention and treatment of gastrointestinal malignancies.

Xudong Huang, PhD (BWH) 
Cancer Imaging Program; Neuro-Oncology Program

Research focus: translational biomedical research paradigms with the potential to contribute to the development of image-based personalized patient care. Together with imaging modality scientists and clinicians, this core lab is designated to provide technical support in design, synthesis, and chemical/biological characterization of molecular imaging (MI) agents, theranostic compounds or therapy-enabling diagnostic (TED) agents for investigators.

John Iafrate, MD, PhD (MGH)
Cancer Genetics Program; Lung Cancer Program

Research focus: translational cancer research with an interest in increasing throughput of genetic assays for clinical implementation. The lab has developed genotyping assays for cancers that will facilitate optimal clinical therapeutic decisions and promote genotype-directed clinical trials.

David Jackman, MD (DFCI)
Lung Cancer Program

Research focus: impact of epidermal growth factor receptor (EGFR) and KRAS genotypes on outcomes with erlotinib or gefitinib therapy. A recent study assessed the impact of EGFR and KRAS mutations on first-line therapy with an EGFR-tyrosine kinase inhibitor (TKI) and compared clinical versus molecular predictors of sensitivity.  Based on results, the lab concluded that EGFR mutation status is associated with sensitivity to treatment with an EGFR-TKI in patients with advanced non-small cell lung cancer and that patients harboring sensitizing EGFR mutations should be considered for first-line erlotinib or gefitinib.

Antoine Elias Karnoub, PhD (BIDMC) 
Angiogenesis, Invasion, and Metastasis Program; Breast Cancer Program

Research focus: understanding the crosstalk that operates between the epithelial and the stromal compartments within breast tumors, with particular emphasis on how these interactions influence cancer metastasis. Recent work indicates that bone-marrow-derived mesenchymal stem cells (MSCs) can home specifically to developing neoplasms where they integrate into the tumor stroma. Current efforts aim to decipher the nature of the cancer-derived systemic signals that affect the bone marrow and how such interactions mobilize MSCs and cause their recruitment to the tumor microenvironment; characterize the nature of the heterotypic interactions that cause the activation of MSCs within the tumor stroma; and elucidate the various mechanisms by which MSCs exert their pro-malignant functions.

Kenneth Kleene, PhD (UMB)
Cancer Cell Biology Program

Research focus: mechanisms of regulation of mRNA translation in mammalian haploid spermatogenic cells. The lab uses transgenic mice to study translational regulation of the sperm mitochondria-associated cysteine-rich protein (Smcp) mRNA, because this is the only approach that provides rigorous in vivo genetic analysis. Currently the team is studying the effects of mutations in predicted regulatory elements on the timing of mRNA translation and are searching for proteins that bind to the 5'UTR and 3'UTR. They make extensive use of comparative genomics to gain insight into the possible mechanisms of post-transcriptional gene expression in haploid spermatogenic cells and to identify sequences to mutate for studies in transgenic mice.

John Koreth, MBBS, DPhil (DFCI)
Leukemia Program; Lymphoma and Myeloma Program

Research focus: need for better control of acute graft-versus-host disease (GVHD) after HLA mismatched peripheral blood stem cell (PBSC) allogeneic transplantation. The lab is currently conducting a Phase I/II trial of bortezomib, tacrolimus and low dose methotrexate for GVHD prophylaxis after HLA mismatched reduced intensity conditioning (RIC) PBSC transplantation for patients with hematologic malignancies. Dose limiting toxicity (DLT) by day 45 after PBSC infusion is the primary endpoint, evaluating both acute bortezomib toxicity and impact on stem cell function. Secondary endpoints include incidence of acute and chronic GVHD. Results to date show that GVHD prophylaxis with bortezomib, tacrolimus and low dose methotrexate after busulfex/fludarabine RIC PBSC transplantation is well tolerated. The low rate of acute GVHD in the HLA mismatched context is encouraging, and additional accrual is ongoing.

Zhe Li, PhD (BWH) 
Breast Cancer Program; Prostate Cancer Program

Research focus: developmental oncobiology of epithelial cancer particularly in understanding how cancer stem cells evolve from normal target cells of cancer through accumulation of mutations and interaction with microenvironments, as avenues for identifying pathways unique to them. This is studied primarily through developing and analyzing novel mouse models of human cancer based on genetic events occurring in patients.

Juan Melero-Martin, PhD (CHB) 
Angiogenesis, Invasion, and Metastasis Program

Research focus: developing cell-based technologies that will enable the engineering of vascularized tissues in vivo using postnatal progenitor cells obtained from patients by non-invasive means. In particular, the focus is on the combined use of bone marrow-derived mesenchymal progenitor cells (MPCs) and human blood-derived endothelial progenitor cells (EPCs) to regenerate adipose and skeletal muscle tissues in vivo lost after tumor resections (such as mastectomy and carcinoma removal). The research conducted aims to address whether generating vascular implants with highly purified and defined MPCs and EPCs will drive tissue development in vivo. The current focus is on formation of adipose tissue and skeletal muscle, but this strategy is envisioned to be applicable to many aspects of regenerative medicine.

Paul Nguyen, MD (DFCI)
Prostate Cancer Program

Research focus: personalizing treatment of men with prostate cancer and optimizing their outcomes. Major areas of focus include: 1) Optimizing risk stratification and treatment selection by analyzing large cross sectional databases to identify risk factors for recurrence, cancer-specific death and all-cause death and to determine which combination of patient, tumor and treatment characteristics would optimize cancer control while minimally impacting health-related quality of life. 2) Technical innovations in the delivery of radiation by working to reduce the side-effects of prostate brachytherapy by using additional imaging and novel devices to decrease the dose delivered to the urethra and rectum. 3) Translational and genetic research using archived prostate tissue at DFCI/BWH and Harvard School of Public Health to identify biomarkers for prostate cancer recurrence and molecular pathways that can potentially be targeted to minimize the risk of recurrence.

 

Brent Passer, PhD (MGH)
Prostate Cancer Program; Translational Pharmacology and Early Therapeutic Trials Program

Research focus: application of replication-competent oncolytic herpes-simplex viruses (oHSV) for the treatment of prostate cancer. Oncolytic HSV-based vectors can replicate within and kill tumor cells (oncolysis), sparing normal cells. One major drawback is its limited capacity to spread intercellularly and kill neighboring cancer cells. To improve the clinical utility of oHSV-based therapies for prostate cancer, the lab's ongoing studies have focused on the identification of chemotherapeutic agents and/or small molecule compounds that modulate important prostate cancer cell pathways and, when paired with appropriate oHSV vectors can increase oncolytic cancer cell destruction. The team has pursued this line of research using two interrelated strategies: 1) Screening several FDA-approved chemotherapeutic agents in conjunction with oHSV to identify a synergistic combination that results in augmented cell death both in vitro and in vivo. 2) Undertook an unbiased high-throughput chemical library screen to identify small molecule compounds that promote augmented oHSV spread in human prostate cancer cells. The coupling of oHSV virotherapy with small molecule discovery has led the lab to uncover novel pathways of viral oncolysis in prostate cancer and moreover, has resulted in increased efficacy in preclinical testing.

Akash Patnaik, MD, PhD (BIDMC)
Prostate Cancer Program; Translational Pharmacology and Early Therapeutic Trials Program

Research focus:  discovery of novel therapeutic targets for advanced prostate cancer. The team is primarily interested in devising approaches to establish the key upstream activators of signaling pathways that are important in advanced prostate cancer, and to determine which drugs that target components of the PI3K and MAPK pathway or its upstream activators are likely to be effective based on the mutational state of the cancer. The lab is currently evaluating several targeted agents in genetically engineered endogenous mouse models of prostate cancer, in parallel to human clinical trials. The long-term goal is to use mouse models with defined genetic mutations to guide selection of patients that will benefit most from the use of these compounds, thus moving the field in the direction of personalized medicine¯. In addition, each drug's efficacy as a single agent and/or in combination with other targeted therapies will also be explored in mouse models. In parallel to the preclinical trials in autochthonous mouse models of prostate cancer, the team is also designing rational early Phase I/II clinical trials, with newly emerging therapies that target different components of these driver pathways.

John Schorge, MD (MGH)
Gynecologic Cancer Program

Research focus: efficacy of primary debulking surgery (PDS) for advanced ovarian cancer. This standard of care was established in the late 1970s and more recently, neoadjuvant chemotherapy (NACT) with interval debulking surgery (IDS) has been increasingly championed. The lab reviewed its experience with newly diagnosed advanced ovarian cancer in order to determine its provision of care.  Based on its studies, the lab concludes that PDS and NACT/IDS have a role in the initial treatment of women with advanced epithelial ovarian cancer and hopes that this data will stimulate discussion of current practices.

Shiladitya Sengupta, PhD (BWH)
Angiogenesis, Invasion and Metastasis Program; Breast Cancer Program

Research focus: understanding the basic relationships at the cellular level that define a pathological state and using this knowledge to develop novel strategies or medicines for treating disease. The lab is probing key questions using novel tools to dissect the complex sugars and connecting what they learn with changes they observe in genetic and protein-signaling. The team then uses this understanding to engineer novel therapeutic approaches for new drug discovery, for hybrid nanotechnology applications for novel therapeutic strategies, and for regenerative medicine using directed stem cell differentiation.

 

Pankaj Seth, PhD (BIDMC) 
Kidney Cancer Program

Research focus: the genetic basis for Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC) syndrome is believed to be a germline inactivating mutation in the gene for the tricarboxylic acid cycle (TCA) enzyme fumarate hydratase (FH), the enzyme that converts fumarate to malate. The inhibition of the TCA results in glycolysis followed by fermentation of pyruvate to lactate, which is a primary source of ATP production as well as the regeneration of NAD+. Within this proposal the lab will screen for and subsequently lead optimize the novel LDH-A specific small molecule inhibitors for the treatment of HLRCC and generate and characterize an orthotopic HLRCC tumor mouse model to better characterize and elucidate the pathways critical in HLRCC while simultaneously providing the ideal animal model for validating the small molecules in vivo.

 

Natasha Stout, PhD (HMS) 
Breast Cancer Program; Outcomes Research Program

Research focus: development and utilization of population-based computer simulation models of the natural history of cancer to inform decision making in health policy and improve population health.

Andrew Wagner, MD (BIDMC) 
Kidney Cancer Program; Prostate Cancer Program

Research focus: identifying critical pathways necessary for soft tissue sarcomas and bone tumors to form and survive and developing novel therapeutics that will be tested both pre-clinically and in early clinical trials. Soft tissue sarcomas and bone tumors represent a heterogeneous group of cancers derived from mesenchymal cells; in general, these tumors are often refractory to standard available chemotherapeutic agents.