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The contributions of sensory nerves to bone metastasis and associated bone pain

Award Number: R01CA238888
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 03/05/2020
PERIOD OF PERFORMANCE END DATE: 02/28/2026

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The contributions of sensory nerves to bone metastasis and associated bone pain - Project Summary Bone metastasis remains a major cause of death among patients with prostate cancer. Unfortunately, current treatments for bone metastases are mainly palliative. A major complication of bone metastasis is bone pain. Although several lines of study have suggested that nerves have a role in cancer progression, and that bone pain and overall survival are negatively correlated, the mechanisms involved remain elusive. We have found that: 1) cancer metastasis to bone or metastatic bone disease enriches sensory nerves that express the neuropeptide calcitonin gene-related peptide (CGRP) in the bone, and that causes bone pain; 2) bone-metastatic cancer cells express elevated levels of calcitonin-receptor like receptor (CRLR); 3) CGRP induces cancer proliferation through the CRLR/p38 pathway; 4) activated FMS-like tyrosine kinase 3 receptor (Flt3) is present in the dorsal root ganglia of mice presenting bone pain indicators; 5) bone-metastatic cancer cells express elevated levels of the Flt3 ligand (FL); and 6) FL induces the sprouting of sensory nerves. We therefore hypothesize that (a) FL derived from bone-metastatic prostate cancer stimulates sensory nerves through Flt3, resulting in cancer-induced bone pain; and (b) CGRP expressed by cancer-associated sensory nerves induces progression of metastatic bone disease through the CRLR/p38 pathway. In this R01 proposal, submitted in response to PAR-16-245, we will: (1) Determine whether bone-metastatic cancer cells increase sensory nerve sprouting and CGRP synthesis in sensory nerves, contributing to cancer-induced bone pain, through the FL/Flt3 axis; and (2) Determine whether CGRP expressed by sensory nerves in bone-metastatic lesions stimulate bone metastatic outgrowth through CRLR/p38. Using an in vitro primary dorsal root ganglia culture system and a unique mouse model of cancer-induced bone pain, will allow us to measure within the same animal: (i) tumor growth, (ii) skeletal innervation, (iii) bone remodeling, and (iv) resultant pain behaviors. Using bone biopsies from patients, we will probe the molecular mechanisms whereby the crosstalk between bone metastatic cancer and sensory nerves controls both progression of bone metastases and development of associated pain. We will use these results to develop a new therapeutic strategy targeting cancer/nerve interactions. In the short term, this study will elucidate new mechanisms of bone metastasis and cancer-induced bone pain. In the long run, a better understanding of how metastatic progression and pain signals influence one another to worsen disease progression will aid in discovering new therapeutic targets for both cancer-induced bone pain and bone metastatic cancer – areas in which current therapies are wanting – to decrease suffering and improve the survival of cancer patients with bone metastases.


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 = $357,702 )
2024	2024	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BLVD	WINSTON SALEM	NC	27157	FORSYTH	USA	Cancer Biology Research	000	5	3/13/2024	NON-COMPETING CONTINUATION	$376,528
2024	2024	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BLVD	WINSTON SALEM	NC	27157	FORSYTH	USA	Cancer Biology Research	001	5	4/30/2024	NON-COMPETING CONTINUATION	-$18,826
														Subtotal = $357,702

Issue Date FY: 2023 ( Subtotal = $368,981 )
2023	2023	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BLVD	WINSTON SALEM	NC	27157	FORSYTH	USA	Cancer Biology Research	000	4	2/23/2023	NON-COMPETING CONTINUATION	$368,981
														Subtotal = $368,981

Issue Date FY: 2022 ( Subtotal = $368,964 )
2022	2022	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BLVD	WINSTON SALEM	NC	27157	FORSYTH	USA	Cancer Biology Research	000	3	3/22/2022	NON-COMPETING CONTINUATION	$338,841
2022	2022	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BLVD	WINSTON SALEM	NC	27157	FORSYTH	USA	Cancer Biology Research	001	3	6/10/2022	NON-COMPETING CONTINUATION	$30,123
														Subtotal = $368,964

Issue Date FY: 2021 ( Subtotal = $376,478 )
2021	2021	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BLVD	WINSTON SALEM	NC	27157	FORSYTH	USA	Cancer Biology Research	000	2	3/5/2021	NON-COMPETING CONTINUATION	$376,478
														Subtotal = $376,478

Issue Date FY: 2020 ( Subtotal = $376,461 )
2020	2020	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BLVD	WINSTON SALEM	NC	27157	FORSYTH	USA	Cancer Biology Research	000	1	3/5/2020	NEW	$376,461
														Subtotal = $376,461

Grand Total All Awards = $1,848,586

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The contributions of sensory nerves to bone metastasis and associated bone pain

Award Number: R01CA238888

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 03/05/2020

PERIOD OF PERFORMANCE END DATE: 02/28/2026

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