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HOST CELL ASSISTED PRIMARY AND METASTATIC TUMOR REGROWTH AFTER CHEMOTHERAPY

Award Number: R01CA041233
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/01/1992
PERIOD OF PERFORMANCE END DATE: 12/31/2014

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HOST CELL ASSISTED PRIMARY AND METASTATIC TUMOR REGROWTH AFTER CHEMOTHERAPY - DESCRIPTION (provided by applicant): Antibodies such as bevacizumab targeting the VEGF-VEGFR-2 pathway of tumor angiogenesis have little or no impact in the treatment of advanced metastatic disease. Instead, clinical benefit is sometimes attained when used in combination with standard chemotherapy regimens. However, even in such cases, the survival benefits are modest. The basis for the chemosensitizing ability of antiangiogenic therapy remain unclear; improvements are likely to come from a better understanding of the mechanisms involved. Hypothesis: Conventional chemotherapy can, in some cases, induce an acute mobilization of bone marrow (BM)-derived cells, including VEGFR-2+ circulating endothelial progenitors (CEPs) which home to and colonize drug treated tumors in large numbers, thus altering the tumor angiogenic microenvironment and stimulating tumor regrowth; this systemic host response can be significantly blocked by co-treatment with a drug such as VEGFR-2 targeting antibodies, or low-dose `metronomic' (antiangiogenic) chemotherapy. Specific Aims: First, a number of chemotherapy drugs will be tested for induction of acute mobilization and tumor homing of CEPs, and whether among those that do, their anti-tumor efficacy is increased by blockade of this host response, using both pharmacologic and genetic approaches. The second aim involves an analysis of chemotherapy-induced BM-derived cell colonization of orthotopic versus ectopic primary transplanted tumors as well as advanced metastases growing in the liver, lungs, or brain. The third aim is devoted to analyzing molecular mechanisms mediating chemotherapy-induced BM-derived cell mobilization and tumor colonization including role of G-CSF, a4¿1 integrin and the CXCR4 chemokine receptor and its ligand SDF-1. The fourth aim will evaluate the contribution of other BM-derived pro-angiogenic CD45+ cell populations having `vascular leukocyte properties', e.g. Gr1+CD11b+ myeloid cells or tie-2 expressing monocytes, among others. Finally, the fifth aim is designed to assess whether surges in CEPs are induced in cancer patients by chemotherapy, including MTD taxanes, and if so, whether bevacizumab blunts such host responses. Significance/Impact: The research links chemotherapy, tumor angiogenesis, antiangiogenic therapy, and the tumor microenvironment in a new way; it will indicate new targets to consider for anti-cancer therapy when combined with chemotherapy, but which may vary with the metastatic environment, and provide new perspectives for the contribution of BM-derived cell populations, including CEPs, in tumor biology and therapy. PUBLIC HEALTH RELEVANCE: The relevance to public health of the proposed research lies in its potential to improve therapeutic outcomes in cancer patients receiving combination treatments of chemotherapy and an antiangiogenic drug or treatment. This is critical since the current benefits of such combination therapies, compared to chemotherapy alone, are very modest, and moreover, come at the expense of increased side effects and rapidly escalating financial costs. The proposed research outlines strategies for obtaining such improvements by exploiting aspects of the systemic bone marrow and blood environments, as well as the local tumor microenvironment, including metastases in different organ sites such as the liver, lung, and brain.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2013 ( Subtotal = $180,805 )
2013	2013	SUNNYBROOK HEALTH SCIENCES CENTRE	2075 Bayview Avenue	TORONTO				CAN	Cancer Treatment Research	000	27	1/18/2013	EXTENSION WITH OR WITHOUT FUNDS	$96,173
2013	2013	SUNNYBROOK HEALTH SCIENCES CENTRE	2075 Bayview Avenue	TORONTO				CAN	Cancer Treatment Research	001	27	6/5/2013	EXTENSION WITH OR WITHOUT FUNDS	$84,632
														Subtotal = $180,805

Issue Date FY: 2012 ( Subtotal = $192,346 )
2012	2012	SUNNYBROOK HEALTH SCIENCES CENTRE	2075 Bayview Avenue	TORONTO				CAN	Cancer Treatment Research	001	26	4/23/2012	NON-COMPETING CONTINUATION	$19,235
2012	2012	SUNNYBROOK HEALTH SCIENCES CENTRE	2075 Bayview Avenue	TORONTO				CAN	Cancer Treatment Research	000	26	12/30/2011	NON-COMPETING CONTINUATION	$173,111
														Subtotal = $192,346

Issue Date FY: 2011 ( Subtotal = $192,346 )
2011	2011	SUNNYBROOK HEALTH SCIENCES CENTRE	2075 Bayview Avenue	TORONTO				CAN	Cancer Treatment Research	001	25	5/13/2011	NON-COMPETING CONTINUATION	$13,880
2011	2011	SUNNYBROOK HEALTH SCIENCES CENTRE	2075 Bayview Avenue	TORONTO				CAN	Cancer Treatment Research	000	25	12/10/2010	NON-COMPETING CONTINUATION	$178,466
														Subtotal = $192,346

Issue Date FY: 2010 ( Subtotal = $198,294 )
2010	2010	SUNNYBROOK & WOMENS COLL HLTH SCIS CTR	2075 Bayview Avenue	TORONTO				CAN	Cancer Treatment Research	001	24	2/18/2010	NON-COMPETING CONTINUATION	$19,829
2010	2010	SUNNYBROOK & WOMENS COLL HLTH SCIS CTR	2075 Bayview Avenue	TORONTO				CAN	Cancer Treatment Research	000	24	12/29/2009	NON-COMPETING CONTINUATION	$178,465
														Subtotal = $198,294

Issue Date FY: 2009 ( Subtotal = $198,294 )
2009	2009	SUNNYBROOK & WOMENS COLL HLTH SCIS CTR	2075 Bayview Avenue	TORONTO				CAN	Cancer Treatment Research	000	23	4/29/2009	COMPETING CONTINUATION	$198,294
														Subtotal = $198,294

Issue Date FY: 2007 ( Subtotal = $192,519 )
2007	2007	SUNNYBROOK HEALTH SCIENCES CENTRE	2075 BAYVIEW AVENUE	TORONTO				CAN	Cancer Treatment Research	000	22	4/9/2007	NON-COMPETING CONTINUATION	$192,519
														Subtotal = $192,519

Issue Date FY: 2006 ( Subtotal = $198,269 )
2006	2006	SUNNYBROOK HEALTH SCIENCES CENTRE	2075 BAYVIEW AVENUE	TORONTO				CAN	Cancer Treatment Research	000	21	4/20/2006	NON-COMPETING CONTINUATION	$198,269
														Subtotal = $198,269

Issue Date FY: 2005 ( Subtotal = $203,040 )
2005	2005	SUNNYBROOK HEALTH SCIENCES CENTRE	2075 BAYVIEW AVENUE	TORONTO				CAN	Cancer Treatment Research	000	20	6/21/2005	NON-COMPETING CONTINUATION	$203,040
														Subtotal = $203,040

Issue Date FY: 2004 ( Subtotal = $203,040 )
2004	2004	SUNNYBROOK HEALTH SCIENCES CENTRE	2075 BAYVIEW AVENUE	TORONTO				CAN	Cancer Treatment Research	000	19	6/23/2004	NON-COMPETING CONTINUATION	$203,040
														Subtotal = $203,040

Issue Date FY: 2003 ( Subtotal = $203,040 )
2003	2003	SUNNYBROOK HEALTH SCIENCES CENTRE	2075 BAYVIEW AVENUE	TORONTO				CAN	Cancer Treatment Research	000	18	6/17/2003	COMPETING CONTINUATION	$203,040
														Subtotal = $203,040

Issue Date FY: 2002 ( Subtotal = $165,843 )
2002	2002	SUNNYBROOK HEALTH SCIENCES CENTRE	2075 BAYVIEW AVENUE	TORONTO				CAN	Cancer Biology Research	000	17	12/21/2001	NON-COMPETING CONTINUATION	$165,843
														Subtotal = $165,843

Issue Date FY: 2001 ( Subtotal = $161,012 )
2001	2001	SUNNYBROOK HEALTH SCIENCES CENTRE	2075 BAYVIEW AVENUE	TORONTO				CAN	Cancer Biology Research	000	16	3/7/2001	NON-COMPETING CONTINUATION	$161,012
														Subtotal = $161,012

Issue Date FY: 2000 ( Subtotal = $156,322 )
2000	2000	SUNNYBROOK HEALTH SCIENCES CENTRE	2075 BAYVIEW AVENUE	TORONTO				CAN	Cancer Biology Research	000	15	5/15/2000	NON-COMPETING CONTINUATION	$156,322
														Subtotal = $156,322

Issue Date FY: 1999 ( Subtotal = $151,768 )
1999	1999	SUNNYBROOK HEALTH SCIENCES CENTRE	2075 BAYVIEW AVENUE	TORONTO				CAN	Cancer Biology Research	000	14	9/16/1999	NON-COMPETING CONTINUATION	$151,768
														Subtotal = $151,768

Issue Date FY: 1998 ( Subtotal = $147,348 )
1998	1998	SUNNYBROOK HEALTH SCIENCES CENTRE	2075 BAYVIEW AVENUE	TORONTO				CAN	Cancer Biology Research	000	13	1/9/1998	COMPETING CONTINUATION	$147,348
														Subtotal = $147,348

Grand Total All Awards = $2,744,286

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HOST CELL ASSISTED PRIMARY AND METASTATIC TUMOR REGROWTH AFTER CHEMOTHERAPY

Award Number: R01CA041233

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 06/01/1992

PERIOD OF PERFORMANCE END DATE: 12/31/2014

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