Robert L. Martuza - US grants

The overall objective is to study the role of hormones and other growth factors in modulating the growth of the tumors associated with the genetic disorder neurofibromatosis (NF). For human meningiomas, we plan to compare the levels of steroid hormone binding by the tumors with their response to the hormones or their antagonists in culture. This will be correlated with the presence or absence of an abnormality of chromosome 22 as detected by karyotypes of early cell cultures and restriction enzyme analysis of DNA isolated directly from tumors. For human Schwann cell tumors (neurofibromas, acoustic neuromas, neurofibrosarcomas) we shall investigate and further characterize the high levels of glial growth factor(GGF)-like activity we have noted in these tumors. We will assess if GGF activity is made in culture by these cells and determine the effects of GGF, sex steroid hormones, and thyroid hormone or their blockers on Schwann cell growth. Further we shall induce Schwann cell tumors in rats with methylnitrosourea and use this model to study the presence of GGF in these tumors and the in vivo effects of the hormonal manipulations noted above. At present there is no medical treatment for NF or for its associated tumors. The development of medical methods to alter tumor growth would benefit not only patients with NF but also non-NF patients with spontaneous tumors of these cell types.

neoplastic transformation; neurofibromatosis; cellular oncology; progesterone; nerve sheath neoplasm; nitrosourea; meningioma; hormone related neoplasm /cancer; neoplasm /cancer diagnosis; tamoxifen; lymphocyte; fibroblasts; hormone regulation /control mechanism; estradiol; estrogens; antitumor antibody; tissue /cell culture; biopsy; electrophoresis; histology; human subject; electron microscopy; microscopy;

We have proposed the development of genetically engineered viral vectors that can selectively and efficiently infect and kill brain tumor cells in situ without harming surrounding brain cells and without causing systemic disease and have focused on conditionally-replicating mutants of herpes simplex virus-1 (HSV-1) which we have genetically engineered to be attenuated for neurovirulence. We developed the vector, G207, a multimutated HSV-1 that conditionally replicates in glioblastoma, malignant meningioma, and other tumors but is non-neuropathogenic in HSV-sensitive mice and subhuman primates. Safety and efficacy studies have been done to allow G207 to be considered for human trial. We have also demonstrated that G207 can induce a specific cell-mediate immune response to tumor cell surface antigens and that this can be boosted with the introduction of cytokines such as IL-12 into a defective vector grown with G207 as a helper virus. We now plan studies to optimize this treatment. We will study factors with possible adverse effects on the clinical use of HSV for brain tumor therapy such as the effects of co- treatment with steroids and the consequences of prior exposure to HSV on the efficacy of HSV-tumor therapy. Tumor models in mice will be used to test. The effects of exposure to steroids or of prior exposure and sero- positivity to HSV. In order to improve the specificity of targeted tumor cell destruction, we also construct and test transcriptionally targeted HSV vectors for selective destruction of cells expressing nestin or midkine. In order to improve the treatment of cells at a distance from virus inoculation, we will also explore the use of HSV vectors expressing cytokines, immune co-stimulatory molecules such as B7-1 and/or a suicide gene, or a combination of these in order to modulate the host immune system to optimize brain tumor therapy with HSV. Through our first grant, we have developed the first HSV vector that can be safely used for brain tumor therapy. Through these studies we expect to create the next generation of HSV vector with improved efficacy and selectivity.

We propose a multidisciplinary research training program in clinical neuro-oncology based at the Massachusetts General Hospital. The primary objective of this two year program is to train physician- scientists capable of providing a critical bridge between brain tumor biology and experimental therapeutics. In order to achieve this objective the training program emphasizes a didactic curriculum in clinical research methodology, cancer cell biology and cancer pharmacology as well as mentor-supervised laboratory and clinical research experience. All clinical and laboratory mentors participating in this training program have extensive experience in neuro-oncology research and training and provide an excellent resource for trainees interested in translational research. All trainees will also have access to senior biostatistical and computing support on all projects. An advisory committee headed by the program director will oversee the training program. In addition to clinical and basic science research facilities at the Massachusetts General Hospital participating institutions include the Brigham and Women's Hospital and the Dana- Farber Cancer Institute. Candidates will include physicians completing clinical training in neurology, neurosurgery, medical oncology and radiation oncology. A qualified pool of applicants from these disciplines can be expected from existing and developing sources. Each trainee will have a dedicated two- year block for research and training with minimal clinical responsibilities. Four postdoctoral positions are requested per year for five years with each trainee making a two year commitment to investigation. Applicants will be selected through active recruitment by the program and individual faculty. We believe that the proposed training program capitalizes on an existing group of outstanding mentors and superb training facilities and will capability to produce productive clinician scientists in neuro-oncology.

DESCRIPTION (provided by applicant): Herpes simplex virus-1 (HSV-1) has many attractive features for further development as an oncolytic and gene transfer vector for prostate cancer therapy. Although many advances have been made in this field in the past decade, we now describe methods to increase the efficacy of treatment using relevant transgenic prostate cancer models mimicking human metastatic prostate cancer. We hypothesize that appropriately chosen chemotherapeutic agents combined with oncolytic HSV vectors will improve anti-tumor efficacy, including after systemic delivery, and that this combination will permit the use of lower, less toxic doses of chemotherapy. We will explore the mechanisms of targeting and anti-tumor efficacy of oncolytic HSV following intravenous delivery. We will study the immune mechanisms of HSV vectors expressing cytokines that can act synergistically to elicit immune destruction of prostate cancer. We hypothesize that oncolytic HSV vectors exert some of their anti-tumor effects by inhibiting angiogenesis within the tumor and that the expression of appropriately chosen cytokines will enhance this anti-angiogenic effect. We will explore these mechanisms of action following both intra-neoplastic and intravenous administration.

[unreadable] DESCRIPTION (provided by applicant): We propose continuation of a multidisciplinary research training program in neuro-oncology based at the Massachusetts General Hospital. The primary objective of this two year program is to train physician- scientists capable of providing a critical bridge between the biological sciences and experimental therapeutics. In order to achieve this objective the training program emphasizes a didactic curriculum in clinical research methodology as well as mentor-supervised laboratory and clinical research experience. All clinical and laboratory mentors participating in this training program have extensive experience in neuro- oncology research and training and provide an excellent resource for trainees interested in translational research. All trainees have access to senior biostatistical and computing support on all projects. An advisory committee headed by the program director oversees the training program. In addition to clinical and basic science research facilities at the Massachusetts General Hospital, the Brigham and Women's Hospital, the Dana-Farber Cancer Institute and Harvard Medical School the program has expanded to include investigators at the Children's Hospital, the Harvard School of Public Health and the Scheppens Eye Research Institute. There is no overlap between our unique grant focused on nervous system tumors and existing K12 and T32 grants at Harvard focused on adult medical oncology. Candidates include physicians completing clinical training in adult and pediatric neuromedical oncology, adult and pediatric neurosurgical oncology, adult and pediatric medical oncology and radiation oncology. A qualified pool of applicants from these disciplines can be expected to grow from existing and developing sources. Each trainee has a dedicated two-year block for research and training with minimal clinical responsibilities. Four postdoctoral positions are requested per year for five years with each trainee making a two year commitment to investigation. Applicants will be selected through active recruitment by the program and individual faculty. We believe that the proposed training program capitalizes on an existing group of outstanding mentors and superb training facilities and will have the capability to produce productive clinician scientists in neuro- oncology. Since the original award in 2002 the program has accepted trainees from 4 oncology disciplines ncluding adult neuromedical oncology, adult neurosurgical oncology, pediatric neuro-surgical oncology and radiation oncology. Each trainee has been assigned a multi-disciplinary mentoring committee to provide guidance and career advice. Graduates from the first cycle of the award have accepted faculty positions and are applying for NIH-based individual research grants. In addition, over the course of the last funding cycle the program has been considerably strengthened by expansion and diversification of the advisory committee, faculty, trainee and resource base. [unreadable] [unreadable] [unreadable] [unreadable] [unreadable]

DESCRIPTION (provided by applicant):: Viral vectors genetically-engineered for replication restricted to cancer cells represent an attractive strategy for prostate cancer therapy because these viruses can replicate and spread in the tumor yet be non-toxic to normal prostate and the surrounding nerves. This overcomes a current challenge of conventional treatments, such as surgery and radiation therapy, and has opened a new avenue for cancer therapy - viral oncolysis- which allows for methods of tumor cell killing that are unique in the field of cancer therapy. Since the mechanisms of viral therapy and the potential toxicities differ from those of standard hormonal or chemotherapy, the possibilities of synergy are worthy of exploration. We have provided data leading to a paradigm shift in thinking about the interactions of pharmaceuticals and/or small molecules with cancer cell pathways and specific oncolytic herpes simplex virus (oHSV) gene mutations. Our overarching hypothesis is that we can identify specific pharmaceuticals and/or small molecules that modulate important prostate cancer cell pathways and, when paired with appropriate oHSV vectors can increase oncolytic cancer cell destruction. We plan to study the following aims: AIM 1: We hypothesize that the small molecules identified by our high throughput screen to enhance oHSV spread in human prostate cancer cells, will synergize in vitro and in vivo to kill prostate cancer;AIM 2: We hypothesize that histone deacetylase inhibitors will sensitize prostate cancer cells to oHSV bearing appropriate mutations through effects on oncogenic signaling pathways;AIM 3: We hypothesize that oHSV's can act as antiangiogenic vectors by attenuating the expression of proangiogenic factors induced by hypoxia and that this effect can be further enhanced by microtubule-spindle poisons. PUBLIC HEALTH RELEVANCE: Current treatment modalities for localized prostate cancer include surgery and radiation therapy, both of which are associated with risks of nerve damage and sexual and/or bladder dysfunction, and other complications. Metastatic prostate cancer also has poor treatment options. In this proposal, we are developing therapeutic modalities to target both local and metastatic disease. This and the lack of good chemotherapeutic responses underscores the public health relevance and importance of developing our proposed strategy as a novel approach to the critical problem of prostate cancer therapy.

Abstract This proposal describes the Research Training Program for Neurology and Neurosurgery Residents at Massachusetts General Hospital (MGH) and Brigham and Women's Hospital (BWH) of Harvard Medical School (HMS). The program combines the exciting variety of collaborative research opportunities available at these campuses with a dedicated core group of neuroscience mentors. Mentors have been carefully selected by the PIs on the basis of research activity, experience guiding clinicians in the early stages of successful research careers, and commitment to this program to develop neurology and neurosurgery residents into effective physician-scientists. A steering committee has been meeting regularly during the creation of this application and will closely oversee all aspects of the resident research training experience.

The Neuro-Oncology Program has been an Established Research Program since 2005. The Program is led by a basic scientist, C. Stiles(DFCI), and a clinician, R. Martuza(MGH), both of whom bring years of leadership experience to their respective roles. The central focus of the Neuro-Oncology Program has been high grade-glioma in adults. The Program has a clinical trials portfolio that offers a range of therapeutic modalities for glioma, including: radiation, tumor vaccines, oncolytic viruses and signal transduction inhibitors. There are also two signal transduction pathways identified as areas of priority: VEGF antagonists and PI3K antagonists. Pediatric neuro-oncology is a growing area of interest. Genetically simple tumors of children have historically shed light on more common, genetically complex adult tumors. One of the significant strengths of the Neuro-Oncology Program in this regard is the presence of a strong pediatric oncology program anchored at DFCI for outpatient care and CHB, a nationally recognized pediatric hospital, for inpatient services, creating a unified pediatric oncology facility that has spanned both institutions for decades. Over the next five years, a goal is to move recent genetic insights from the bench to the bedside in order to improve the standard of clinical care and enable genetically-informed clinical trials. The Program plans to develop CLIA-certified assays for all actionable genetic lesions in high-grade glioma and to apply these assays to every tumor resected at DF/HCC hospitals. There are 93 members in the Program drawn from all seven DF/HCC member institutions. They represent 13 departments of HMS and one department of HSPH. Collectively, members receive over $22.6 million in cancer-relevant funding, of which $8.1 million was from NCI and $10 million was from other peer-reviewed sponsors. During the project period (2006 to 2010), members published 997 articles in peer-reviewed journals, of which 18% were intra-programmatic, 33% were inter-programmatic, and 21% were interinstitutional. At the time of the CCSG renewal in 2005, the Program received a merit score of excellent to very good.