The following investigators were awarded Geoffrey Beene Cancer Research grants in 2013:
Human Oncology and Pathogenesis Program
Project Title: Somatic genetic alterations in the pathogenesis and therapy of histiocytic disorders
Project Abstract: The histiocytic disorders are a collection of diseases characterized by an accumulation of white blood cells called macrophages and/or dendritic cells in various tissues throughout the body. These diseases present with a wide array of clinical manifestations and have a variety of subtypes based on the microscopic appearance of white blood cells. Because of the rarity of each individual subtype of histiocytic disease and their very heterogeneous clinical presentations, the clinical experience and biologic understanding of many of these diseases has been limited. A major breakthrough in the biology and therapy of these disorders came with a recent discovery that 40 to 50 percent of patients with the most common histiocytic disorders have mutations in the oncogene BRAF. Based on this finding, we organized a group of physicians and scientists at Memorial Sloan-Kettering committed to identifying the genetic abnormalities underlying the histiocytic disorders and treating these patients as part of monitored clinical trials using approaches targeting these genetic alterations. Thus far we have made great progress in the treatment of BRAF-mutant histiocyte patients with the mutant BRAF inhibitor vemurafenib and found new genetic alterations, which are promising targets for novel therapies for additional histiocytic-disorder patients.
Human Oncology and Pathogenesis Program
Project: Generation of personalized models of prostate cancer for correlates of disease response and progression
Project Abstract: Cancer cells growing in the laboratory are extensively used to study tumorigenesis and therapy. Prostate cancer cells are uniquely difficult to grow in the laboratory, hampering the ability for researchers to study the mechanisms of disease and drug resistance. Using newly developed methods to grow prostate cancer cells that are directly derived from patient biopsies, we propose to establish a panel of lines from patients entering clinical trials in prostate cancer. We will characterize these lines for genetic mutations and drug sensitivity to study the genetic basis of tumor growth and drug resistance.
Department of Pediatrics
Project: Bispecific antibody to engage T cells for cancer therapy
Project Abstract: T lymphocytes are ferocious killers. They kill serially and while killing, they multiply, setting up killer colonies at the sites where they encounter tumor cells. Unfortunately many tumor cells, including neuroblastoma, are immune to these killer T cells. Bispecific antibodies (BsAb) are engineered to carry the binding sites of two different antibodies – one site is to bind to T cells; the other is to handcuff T cells to the tumors. Now, T cells can do what they are trained to do – be killing machines. With BsAb, tumors can no longer escape the immune system. First, the expression of antigens called HLA on tumors is no longer required. Moreover, nearly all T cells can be recruited, and they no longer need to be prior-educated or “primed” to the tumor. Early studies in leukemia and lymphoma have shown dramatic positive clinical results. In this proposal, a BsAb to retarget T cells to the ganglioside GD2 on human tumors will be developed into a clinical drug, and be made ready for first-in-human clinical trial. Since GD2 is present on many pediatric tumors including neuroblastoma, osteosarcoma, Ewing’s family of tumors, and rhabdomyosarcoma, this drug will be useful for some of these difficult-to-cure childhood cancers. If it is proven safe and effective, this BsAb may have broad application to adult cancers with GD2 present, such as small cell lung cancer, melanoma, and brain tumors.
Human Oncology and Pathogenesis Program
Project: Clinically targeting ETV1 in advanced gastrointestinal stromal tumor (GIST)
Project Abstract: Gastrointestinal stromal tumor (GIST) is characterized by activating mutations in the KIT or PDGFRA receptor tyrosine kinases. Despite the clinical success of imatinib, nearly all advanced GIST patients develop imatinib resistance and eventually die of their disease. We have recently discovered that ETV1 – an ETS family transcription factor and a well-established oncogene involved in recurrent genomic alterations in prostate cancer, Ewing sarcoma, and melanoma – plays a critical role and cooperates with mutant KIT/PDGFRA in GIST pathogenesis. Here, we propose to examine a novel therapeutic strategy that simultaneously targets both the mutant KIT/PDGFRA and ETV1 in preclinical murine GIST models and in a phase Ib/II clinical trial in advanced GIST patients. We will examine the efficacy and imatinib/MEK inhibitor-resistance mechanisms of this dual-targeting strategy and develop predictive therapeutic biomarkers using biospecimens derived from the murine models and the clinical trial. We believe that this strategy, if successful, has the potential to change the landscape of clinical practice in GIST management and has important therapeutic implications in other ETV1-dependent malignancies.
Cell Biology Program
Project Title: Inactivation of neogenin in castration-resistant prostate cancer
Project Abstract: Once prostate cancer has become refractory to antiandrogen therapy and metastatic, it cannot be effectively cured. The molecular pathways underlying prostate cancer progression to this advanced stage are incompletely understood. We have observed that the cell adhesion receptor neogenin is inactivated in a fraction of hormone-refractory prostate tumors. We propose to elucidate the molecular mechanisms by which loss of neogenin induces prostate cancer progression and metastasis and to examine whether these mechanisms operate in human prostate cancer. The results of these studies may lead to the identification of novel targets for the therapy of AR-independent prostate cancer.
Project: Quantitative approaches for the mechanistic analysis of tumor cell killing by cytotoxic lymphocytes
Project Abstract: Cytotoxic T lymphocytes (CTLs) fight cancer by recognizing and destroying tumor cells. This proposal describes experiments aimed at learning how CTLs carry out this killing process. The information gained from our study will aid in the development of strategies to use CTLs for antitumor immunotherapy.
Department of Medicine
Project: Combined JAK2/HSP90 inhibition in primary myelofibrosis, post-essential thrombocythemia myelofibrosis, and post-polycythemia vera myelofibrosis
Project Abstract: The Philadelphia chromosome (Ph)-negative myeloproliferative neoplasms (MPNs) include myelofibrosis (MF), polycythemia vera (PV) and essential thrombocythemia (ET). Mutations in the JAK2 gene occur in the majority of MPN patients, which has led to efforts to target this mutation with JAK2 inhibitors. The JAK1/2 inhibitor ruxolitinib has been approved for the treatment of MF. While JAK inhibitor therapy relieves symptoms in the majority of MF patients, there is no evidence that these inhibitors can induce remission of the disease. Thus, other agents are needed that can target JAK2. Hsp90 is a protein chaperone that stabilizes JAK2. We previously demonstrated that JAK2 associates with Hsp90, and that inhibition of Hsp90 leads to degradation of JAK2. Our preliminary studies suggest that combined Hsp90/JAK2 inhibition results in more potent JAK2 inhibition. We therefore seek to determine the effect of combined Hsp90 and JAK2 inhibition in preclinical studies and in MPN patients with the goal of improving the outcome of patients with MPNs.
Department of Medicine
Project: TFIIH complex somatic mutations as biomarkers of platinum chemotherapy sensitivity
Project Abstract: While platinum-chemotherapy has been long used in oncology, most patients do not derive dramatic benefits. Newly identified DNA repair gene mutations in urothelial carcinoma appear to be associated with high levels of sensitivity to cisplatin chemotherapy in muscle-invasive urothelial tumors. This project will determine whether these findings predict response to platinum chemotherapy drugs in metastatic urothelial carcinoma and begin to explore whether these or similar mutations in other cancer types predict platinum treatment responses. In addition, laboratory investigations will explore the molecular underpinnings of these findings. The ultimate goal of this project is to determine whether these mutations can be used to predict which tumors will respond to platinum chemotherapy, allowing better selection of patients for chemotherapy treatment.
Molecular Pharmacology and Chemistry Program
Project: Functional consequences and therapeutic implications of RAF-dimer signaling in cancer
Project Abstract: Activation of the ERK signaling pathway occurs in at least half of human cancers and is controlled by a protein called RAF. RAF can exist as a single protein (monomer) or a pair of proteins bound together (dimer); in most tumors, activation occurs via dimers. Inhibitors of RAF monomers have been developed that have remarkable clinical activity in melanoma, but no inhibitors of RAF dimers currently exist. We have now identified the first known inhibitor of RAF dimers and found that it inhibits some tumors that are driven by this protein. Our grant is focused on understanding how this compound works, using this information to make better drugs, and developing these drugs as cancer therapeutics.
Project: Investigating the role of transcription factor Zbtb32 in the NK cell response against tumor establishment and metastasis
Project Abstract: Natural killer (NK) cells recognize and destroy transformed host cells in a process termed tumor immunosurveillance. Humans lacking NK cells or NK cell function have severe health complications due to certain cancers and viral infections. The general goals of my research program are to understand the molecular mechanisms behind NK cell responses against cancer and infectious pathogens. Because the transcription factor Zbtb32 is critical for NK cell activation and proliferation, we will investigate the role of Zbtb32 in the generation of a robust immune response against tumor establishment and metastasis. The studies in this proposal will uncover the biological pathways mediated by Zbtb32 and provide a framework for manipulating powerful NK cell responses in the clinic to target cancer.
Department of Radiology
Project: Theranostics of neuroendocrine tumors with somatostatin antagonists
Project Abstract: The goal of this study is to develop a new therapy for neuroendocrine tumors (a group of tumors that can arise from hormone-producing cells throughout the body). The therapy is based on a novel class of molecules (somatostatin receptor antagonists) that can selectively deliver radiation to these tumors. The study will evaluate how much radiation can be delivered safely in patients and how well tumors respond to this therapy.