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Research Studies

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Please click on the "donate to this grant" link at the end of the description of each grant below


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Grant No. DT06PA-001 | Therapeutic inhibition of angiogenesis in canine tumors

Principle Investigator:

Andrei Thomas-Tikhonenko, Ph.D.
Chair, Cancer Biology Graduate Program
Chief, Division of Cancer Pathobiology
Department of Pathobiology
University of Pennsylvania

The National Canine Cancer Foundation has restructered this grant with Dr. Modiano.  Instead of one large grant, we are funding the entire study in a series of smaller grants so that we can move the research ahead in a more expedient manner. Listed below are the grants funded and the most recent in the series of grants to be funded.

First in the Series of Grants

Amount of Grant:
$150,000  THIS GRANT HAS BEEN FULLY FUND THROUGH DONATIONS AND SUPPORT FROM THE BRUISER 5K FUND, THE LANCE MEMORIAL FUND, THE TEXAS SHOOT OUT, CHASE AWAY K9 CANCER FUND AND DONATIONS FROM OUR SUPPORTERS.

Title:
Therapeutic inhibition of angiogenesis in canine tumors.

Abstract:
During the last decade, human medicine has witnessed the emergence of the new generation of cancer drugs, which were rationally designed to block pathways crucial to tumor growth. One eloquent example is the inhibitors of angiogenesis (the ingrowth of new blood vessels into the tumor). All tumors need a blood supply to provide rapidly dividing cancerous cells with oxygen and nutrients. The task of generating new vessels is two-fold: it requires an increased production of pro-angiogenic molecules and a decreased production of anti-angiogenic molecules. The chief proangiogenic molecule is a protein called VEGF (for Vascular Endothelium Growth Factor.) The chief anti-angiogenic molecule is a protein called TSP (for ThromboSPondin.) That most tumors go to extraordinary lengths to overproduce VEGF and silence TSP attests to the significance of these molecules.

In our proposal we will focus on three complementary Aims.

1. To generate canine “VEGF trap” proteins capable of binding and sequestering this pro-angiogenic factor. This will be achieved by artificially truncating naturally occurring cell membrane-bound form of VEGF sensors (known as VEGF receptors). The truncated forms typically do not possess pro-angiogenic activities. Instead they channel VEGF into dead-end protein-protein interactions.

2. To test anti-angiogenic activities of polypeptides based on the canine thrombospondin-1 protein. Experimental tumors will be treated with either polypeptides themselves or DNA fragments encoding such peptides.

3. To identify molecules capable of re-activate endogenous (tumor-produced) thrombospondin.

Two classes of molecules are under investigation:
a) compounds that directly increase the half-life of thrombospondin-1 messenger RNA; b) compounds that increase the half-life of the protein called p53, which is the major activator of thrombospondin.

By the end of the 3d year of NCCF-funded research, we expect to have begun clinical trials involving at least some of these newly developed therapeutics. By the very nature of anti-angiogenic compounds, they can be applied towards a wide range of common canine neoplasms ranging from Hemangiosarcoma to breast cancers to B-lymphomas, which collectively account for the majority of cancer-related deaths in dogs.

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Grant No. DM06CO-002 | Innovative Molecular Targets for Prevention and Treatment of Canine Hemangiosarcoma

Principle Investigator:

Jaime F. Modiano, V.M.D., Ph.D.
Perlman Professor of Oncology/Comparative Medicine
College of Veterinary Medicine and Masonic Cancer Center
University of Minnesota

The National Canine Cancer Foundation has restructered this grant with Dr. Modiano.  Instead of one large grant, we are funding the entire study in a series of smaller grants so that we can move the research ahead in a more expedient manner. Listed below are the grants funded and the most recent in the series of grants to be funded.

First in the Series of Grants

Amount of Grant:
$25,000 - Fully funded- THIS GRANT HAS BEEN fULLY FUND THROUGH DONATIONS AND SUPPORT FROM THE LANCE MEMORIAL FUND AND THE TEXAS SHOOT OUT.

Title:
Innovative Molecular Targets for Prevention and Treatment of Canine Hemangiosarcoma

Abstract:
Recent work indicates that some cancers arise from cells that acquire properties of self-renewal that resemble those seen in stem cells. These cells, called “cancer stem cells” or “tumor-initiating cells” have been isolated from a variety of blood-derived tumors (leukemias and multiple myeloma) and solid tumors (colon cancer, breast cancer, brain tumors, and others). However, it is not known if the origin of hemangiosarcoma in dogs (or angiosarcoma in people) conforms to this cancer stem cell theory. We have shown that there is a subpopulation of cells in canine hemangiosarcoma tumors that express cell surface proteins that are consistent with those seen in a cell type called “hemangioblast” that is predicted to exist in the bone marrow as an early progenitor cells that can give rise to both endothelial (blood vessel lining) cells and blood elements (red cells, white cells, and platelets). Although the existence of hemangioblasts remains a matter of some controversy, there is evidence to support their existence in some species. Here, we propose to test the hypothesis that the “progenitor” cells in hemangiosarcoma resemble hemangioblasts both functionally and by assessing their molecular profiles. We predict that hemangiosarcoma cells will show both multipotency and the ability to regenerate cell lines in culture.

Second in the Series of Grants

Amount of Grant:
$28,000 - Fully fund THIS GRANT HAS BEEN fULLY FUND THROUGH DONATIONS AND SUPPORT FROM THE TEXAS SHOOT OUT AND THE CHASE AWAY K9 CANCER FUND.

Title:
Tumor-Environment Interactions in Canine Hemangiosarcoma - Principal Investigators: Leslie Sharkey, DVM, PhD, DACVP and Jaime F. Modiano, VMD, PhD

Abstract:
Canine hemangiosarcoma (a tumor of blood vessel lining cells) represents one of the deadliest cancers that affect dogs. While there is predilection for certain organs such as the spleen, skin and heart, these tumors can arise in any organ, they are highly metastatic, and they are poorly responsive to conventional therapies. The common prevalence and poor response of this tumor have led many groups to test new experimental therapies, including metronomic chemotherapy, various anti-angiogenic strategies, the histone deacetylase inhibitor (DNA modifier) SAHA (vorinostat), immunotherapeutic approaches, protein tyrosine kinase inhibitors, and others. While these approaches have reported anecdotal success, none have shown conclusively that they can produce equal or better responses than the current standard of care (surgery plus cytotoxic chemotherapy).

Our group has devoted considerable resources to understand the etiology of hemangiosarcoma at the cellular and the molecular level, hoping to generate new knowledge that might lead to more successful management of this cancer. Our preliminary results suggest that a specialized cell type that participates in blood vessel formation (hemangioblast) may give rise to the tumors. These cells have the potential to alter their surroundings to maximize their potential for growth and survival. Furthermore, they have certain features that could be responsible for the resistance of these tumors to conventional chemotherapy drugs. These findings have encouraged us to be circumspect about the dogma surrounding hemangiosarcoma. In fact, these tumors are complex tissues, and it is not clear which components within this tissue arise from the malignant population and which components are derived from normal cells recruited into (or responding against) the malignant cells. In fact, it is well established that many tumor lesions are comprised of a mix of malignant and non-malignant origin cells, and that the behavior of the non-malignant origin cells can be pivotal in influencing the biological behavior of neoplastic cells and thus patient prognosis. This raises several important questions regarding the aggressive biological behavior of canine hemangiosarcoma. To begin to answer how the local tissue microenvironment contributes to the biological behavior of canine hemangiosarcoma, we propose to define which components of canine hemangiosarcoma lesions arise from a malignant cell population and which components are derived from normal cells using in vivo models. Increasing evidence suggests that many cancers rely on the activity of normal surrounding tissue to achieve their malignant phenotype, and modification of their environment may influence the biological behavior of the tumor. Once we have a better understanding of the interactions between the malignant hemangiosarcoma cells and the normal supporting microenvironment cells (inflammatory, angiogenic, stromal, and nerves), will we be able to determine how to develop strategies to target microenvironmental factors to improve the therapeutic options for this disease.

Third in the Series of Grants

Amount of Grant:

$55,550 - Fully Funded. THIS GRANT HAS BEEN fULLY FUND THROUGH A GNEROUS GRANT BY PETCO/BLUE BUFFALO AND ADDITIONAL BY DONATIONS AND SUPPORT FROM THE TEXAS SHOOT OUT.

Title:
Tumor-Environment Interactions in Canine Hemangiosarcoma - Principal Investigators: Jaime F. Modiano, VMD, PhD

Abstract:

This application is designed to continue past work supported by NCCF to define the molecular pathogenesis of canine hemangiosarcoma and develop rational and effective strategies for prevention, diagnosis, and treatment.

Our group has devoted considerable resources to understand the etiology of hemangiosarcoma at the cellular and the molecular level, helping to generate new knowledge that might lead to more successful management of this cancer. The underlying theme of work supported by NCCF in our laboratories has focused on answering three fundamental questions:

1.   Does the local tissue microenvironment contribute to the biological behavior of canine hemangiosarcoma?

2.   Does the local microenvironment of hemangiosarcoma differ among tumors arising at different sites or in different organs (for example, spleen, heart, liver, skin)?

3.   Can we target the microenvironment to deprive the tumors of specific factors that are essential for tumor growth and survival, or to eliminate the capacity of the tumor to spread to distant sites?

Data from Milestone Project 2 showed that hemangiosarcoma cells have broad potential for growth at various sites in xenogeneic hosts (immunocompromised  mice) with no apparent preferences based on their site of origin. This project also supported work that suggests canine hemangiosarcoma conforms to the hierarchical (“cancer stem cells”) model of cancer.

Our data suggest that local tissue microenvironment does influence growth and progression of canine hemangiosarcoma, although the precise mechanisms that account for this remain to be determined. On the other hand, there appear to be no major differences between hemangiosarcoma cells that arise from distinct anatomical sites with regard to growth potential and tumor formation, although it remains possible that the observed absence of site specificity was due to selection of tumors with high metastatic potential. The potential to target the microenvironment for therapy is the focus for this Milestone 3 project. The hypothesis is that preferential bias towards use of different chemokine receptors alters the growth, differentiation and/or lineage commitment of hemangiosarcoma. The results from this project will guide development of subsequent milestones, with the ultimate goal to fundamentally understand the disease in order to develop effective means for timely diagnosis and therapy.

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Grant No. DK06CA-005  | Treatment of canine lymphoma with liposome encapsulated doxorubicin bound to a high affinity ligand

 

Principle Investigator:
Dr Michael S. Kent
Assistant Professor
Center for Companion Animal Health (CCAH)
Department of Surgical and Radiological Sciences
School of Veterinary Medicine
University of California, Davis

Phase One:
$50,000  Fully funded - THIS GRANT HAS BEEN fULLY FUND THROUGH DONATIONS AND SUPPORT FROM THE SUNI FUND AND THE LANCE MEMORIAL FUND.

Title:
Treatment of canine lymphoma with liposome encapsulated doxorubicin bound to a high affinity ligand.

Abstract:
We have recently identified a small chemical molecule that can bind specifically and extremely strongly to a protein on the cell surface of lymphoid cancer cells (Non-Hodgkins lymphoma and lymphocytic leukemia).

The protein receptor is called a4ß1 integrin receptor and is present in an active form on lymphoid cancer cells. Our chemical molecule only binds to active form of the protein. We named this molecule 2A and we believe 2A, when linked to potent cancer drugs, can effectively deliver the cancer drugs to cancer cells and not normal cells; therefore we expect the 2A-drug conjugate to be very effective in killing cancer cells while sparing normal cells. The goal of this clinical trial is to test this targeted therapy in dogs with Non-Hodgkins lymphoma.

Further we aim to correlate the binding of the targeted protein 2A to response and overall survival in patients treated with Doxil-2A.

Phase Two:
$100,000 Second year. - Due to the success of the first phase of this study we will be funding a second phase in 2011.

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