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Control of lethal prostate cancer with a bispecific av and a5b1 integrin antibody

Award Number: R01CA245864
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/01/2020
PERIOD OF PERFORMANCE END DATE: 05/31/2025

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Control of lethal prostate cancer with a bispecific av and a5b1 integrin antibody - ABSTRACT The majority of the 300,000 annual deaths worldwide from prostate cancer are strongly attributed to bone metastasis because the skeleton is the exclusive site of clinical disease in the majority of men with advanced illness. There is a fundamental gap in our knowledge of the mechanisms that underpin the efficient and life- threatening colonization of the bone microenvironment by prostate cancer cells. Our long-term goal is to develop novel therapeutic strategies based on a molecular understanding of the pathophysiology of bone metastases in order to significantly improve survival and quality of life outcomes in prostate cancer. Our laboratory studies implicate two different but functionally related integrins expressed by prostate cancer cells in their homing, survival and lethal spread within the bone microenvironment. The rationale of this study is that a bispecific antibody that simultaneously targets these 2 integrins would optimally neutralize their function via its cross-linking mechanism of action and deliver an efficacious therapeutic strategy. Accordingly, a first-in-class bispecific antibody targeting these integrins demonstrated superior antitumor activity compared to monospecific antibodies alone or in combination. A distinct molecular mechanism of action for the bispecific antibody was defined. Following treatment with either or both monospecific integrin antibodies, adaptive upregulation of the integrins was seen whereas by contrast, downregulation of integrins followed bispecific antibody treatment via induction of internalization and lysosomal degradation of integrins. Our hypothesis is that the bispecific integrin antibody will halt the life-threatening progression of prostate cancer in the bone microenvironment. We plan to evaluate this hypothesis with three specific aims. First, we plan to assess the efficacy of the bispecific antibody compared to monospecific antibodies in distinct animal models of bone metastases that replicate key dimensions of the clinical disease: seeding of the bone marrow, interaction with human bone-derived stromal cells, accelerated growth and secondary dissemination from bone, and finally, generation of an osteoblastic phenotype. Secondly, we will further define the mechanism of action of the bispecific integrin antibody by assessing its impact on epithelial-mesenchymal transition, anoikis and clonogenic survival. Finally, we will determine the organ-specificity of the expression of the two integrins by comparing the expression of these integrins in bone metastases from prostate cancer and other solid tumors to metastases found in lymph nodes and visceral organs. Our innovative therapeutic strategy to disable the molecular mechanisms of colonization of the bone microenvironment by prostate cancer is significant because it has the potential to significantly prolong survival and improve quality of life of patients with prostate cancer. Solid tumors that colonize bone such as breast cancer may leverage the same molecular pathways, expanding the potential significance and impact of the bispecific antibody strategy in biomarker-supported clinical trials to follow.


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: 2024 ( Subtotal = $497,137 )
2024	2024	TUFTS MEDICAL CENTER PARENT, INC.	800 WASHINGTON ST	BOSTON	MA	02111	SUFFOLK	USA	Cancer Treatment Research	000	5	5/6/2024	NON-COMPETING CONTINUATION	$497,137
														Subtotal = $497,137

Issue Date FY: 2023 ( Subtotal = $497,984 )
2023	2023	TUFTS MEDICAL CENTER, INC.	800 WASHINGTON ST	BOSTON	MA	02111	SUFFOLK	USA	Cancer Treatment Research	000	4	5/15/2023	NON-COMPETING CONTINUATION	$497,984
														Subtotal = $497,984

Issue Date FY: 2022 ( Subtotal = $467,360 )
2022	2022	TUFTS MEDICAL CENTER, INC.	800 WASHINGTON ST	BOSTON	MA	02111	SUFFOLK	USA	Cancer Treatment Research	000	3	5/17/2022	NON-COMPETING CONTINUATION	$467,360
														Subtotal = $467,360

Issue Date FY: 2021 ( Subtotal = $473,941 )
2021	2021	TUFTS MEDICAL CENTER, INC.	800 WASHINGTON ST	BOSTON	MA	02111	SUFFOLK	USA	Cancer Treatment Research	000	2	5/27/2021	NON-COMPETING CONTINUATION	$473,941
														Subtotal = $473,941

Issue Date FY: 2020 ( Subtotal = $473,941 )
2020	2020	TUFTS MEDICAL CENTER, INC.	800 WASHINGTON ST	BOSTON	MA	02111	SUFFOLK	USA	Cancer Treatment Research	000	1	5/28/2020	NEW	$473,941
														Subtotal = $473,941

Grand Total All Awards = $2,410,363

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Control of lethal prostate cancer with a bispecific av and a5b1 integrin antibody

Award Number: R01CA245864

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 06/01/2020

PERIOD OF PERFORMANCE END DATE: 05/31/2025

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