Departments of Medicine/Immunology Tumor Immunology Program

Current Research Areas
 

• Preclinical evaluation of combinatorial anti-angiogenic and other targeted therapeutic approaches on leukemia/lymphoma dissemination and growth in vivo
• Role of marrow microenvironment in mediating drug-resistance in acute leukemia
• Interactions of VEGF with other immune-mediated processes promoting malignant hematological growth
• Correlation of angiogenic factor expression levels with biological and clinical features of leukemia/lymphoma patients
• Development of small animal imaging techniques for vascular and angiogenic assessment of in vivo models of human hematological malignancies

Angiogenesis in Hematological Malignancies
Introduction

Leukemia and lymphomas are malignant diseases arising from abnormal hematopoietic and lymphoid cells with increased proliferation in bone marrow and lymph node sites. The cornerstone of therapy for these diseases remains intensive chemotherapy and/or stem cell transplantation with cure rates ranging from 20-50%.

Targeting the tumor microenvironment rather than rapidly dividing genetically aberrant cancer cells, represents a paradigm shift in oncology. Over the last three years, inhibition of vascular endothelial growth factor (VEGF), the most potent factor promoting tumor angiogenesis, has been shown to prolong survival in patients with colorectal, lung, breast, and renal cancers. Despite this, anti-VEGF agents have not been extensively explored in hematological cancers, possibly due to the misconception that blood cancers do not rely on blood vessels for growth.

Our research is focused on understanding how angiogenesis contributes to malignant hematopoiesis and translating these findings into clinical trials targeting angiogenic pathways for leukemia and lymphoma. High levels of VEGF and VEGF receptors (VEGFR) in conjunction with increased numbers of blood vessels have been found in marrows and lymph nodes of leukemia/lymphoma patients. VEGF exists as many isoforms interacting with three VEGFR (R-1, R-2, R-3) to directly mediate vascular/lymphatic endothelial and normal as well as malignant hematopoietic cell growth (FIGURE).

We are presently investigating the effects of angiogenic growth factors (and angiogenic inhibitors) on human leukemia and lymphoma cell growth using cultured cell lines and primary patient leukemia. Techniques include Q- and RT-PCR, Western blots, flow cytometry, gene transfection, shRNA knockdown, and cytotoxic/proliferation assays. Our data has shown that high VEGF levels are found in a significant proportion of acute myeloid leukemia (AML) patient samples. Overexpression of VEGF in human AML cells contributes to enhanced leukemia growth in vivo, and inhibition of VEGF with an anti-VEGF antibody or decoy VEGF receptor significantly prolonged survival of human AML in vivo in preclinical models. VEGF inhibition was more effective than maximally tolerated chemotherapy in these models. Tumor cells with high VEGF expression also exhibited greater anti-tumor responses to anti-VEGF therapy than malignant cells with low VEGF expression.

Based on these results, we hypothesize that VEGF-mediated angiogenesis is a key contributor to in vivo leukemia growth in a significant subset of AML patients. Because the primary sites of leukemia in human patients are the bone marrow and blood, we have developed immunodeficient mouse xenograft models engrafted with human leukemia cells in the bone marrow, peripheral blood, and other sites. Use of these animal models will:
a) confirm the preclinical efficacy of these novel therapeutic agents in human disease;
b) test promising therapeutic agents alone and in combination with conventional chemotherapy; and
c) identify characteristics of disease biology which may predict response to therapies in future clinical investigations. We are utilizing small animal bioluminescent and other imaging techniques as a non-invasive means of monitoring disease progression and dissemination in diverse organ sites during real-time interventions. The development of these preclinical recapitulating the biology of cultured and primary leukemia patient samples in vivo provides us with a relevant model to rapidly screen and translate our results into early stage clinical trials.

Our research is funded by the American Cancer Society, Alliance Foundation (RPCI), Szefel Foundations (RPCI), and the Buswell Research Foundation grants (SUNY-UB School of Medicine).