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STRESS UNDERMINES IMMUNE STIMULATION: MECHANISMS & BIOLOGICAL SIGNIFICANCE

Award Number: R01CA172138
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/22/2013
PERIOD OF PERFORMANCE END DATE: 05/31/2019

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STRESS UNDERMINES IMMUNE STIMULATION: MECHANISMS & BIOLOGICAL SIGNIFICANCE - DESCRIPTION (provided by applicant): We recently reported that stress can prevent immuno-stimulatory agents (ISAs) (e.g., IL-12) from activating cell-mediated immunity (CMI) and from controlling cancer metastasis in animal models. This phenomenon may partly account for the lesser success of ISA use in cancer patients relative to animal studies, as unlike animals in preclinical studies, cancer patients often experience marked anxiety and stress while treated with ISAs. This problem may be especially critical during the short peri-operative period in cancer patients, when immune stimulation could potentially promote patients' ability to control residual tumor progression after tumor removal, but deleterious psychological and physiological stress responses are heightened. Additionally, even if successful immune stimulation is achieved pre-operatively, surgery often causes profound suppression of CMI, rendering pre-operative immune stimulation ineffective. To overcome these obstacles, in the proposed study we aim to: (i) elucidate neuroendocrine, immune, [and tumor-related cellular and molecular] mechanisms via which various stressors dampen the beneficial effects of different ISAs; (ii) assess the biological significance of this phenomenon, using several models of cancer metastasis that bear clinical relevance; (iii) devise and test prophylactic approaches of potential clinical applicability to circumvent these deleterious effects of stress on immune stimulation; and (iv) in the context of primary tumor excision, compose integrated regimens that enable both successful peri-operative immune stimulation under stressful conditions, as well as the blockade of the deleterious effects of surgery on immunity and on resistance to tumor metastasis. To achieve these goals we will use psychological and physiological stress paradigms and study the efficacy of [two] different clinically approved ISAs, which are novel synthetic compounds (CpG-C, & GLA) that are under clinical investigation and can be used with minimal adverse effects during the peri-operative period. The prevention of the deleterious effects of surgery [itself] wil build on our recently-devised pharmacological intervention based on a COX2 inhibition and a �-adrenergic blockade, which is now approved for clinical testing. Immune indices to be studied will include recently- recognized immune mechanisms that are critical for controlling tumor progression, including marginating- pulmonary and marginating-hepatic immunocytes, killer dendritic cells, memory-like NK cells, and several molecular determinants of anti-metastatic CMI. Cancer progression will be studied employing models of breast, colon, lung, and skin cancer metastasis in mice and rats. [Excised primary tumors will be analyzed], and metastatic development will be repeatedly monitored by bioluminescence-based imaging. The clinically important outcome of survival rates will also be assessed in orthotopic models of spontaneous metastasis. The proposed studies will strive both to elucidate basic mechanisms of interaction between stress and immune stimulation at the systemic and molecular levels, and to translate these insights into clinically feasible therapeutic approaches that can be used in cancer patients undergoing curative cancer resection.


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: 2022 ( Subtotal = $30 )
2022	2017	TEL AVIV UNIVERSITY	55 LEBANON HAIM	TEL AVIV-JAFFA				ISR	Cancer Cause and Prevention Research	000	5	9/26/2022	NON-COMPETING CONTINUATION	$30
														Subtotal = $30

Issue Date FY: 2020 ( Subtotal = -$7,887 )
2020	2017	TEL AVIV UNIVERSITY	55 LEBANON HAIM	TEL AVIV-JAFFA		006905904		ISR	Cancer Cause and Prevention Research	000	5	1/2/2020	NON-COMPETING CONTINUATION	-$7,887
														Subtotal = -$7,887

Issue Date FY: 2017 ( Subtotal = $199,019 )
2017	2017	TEL AVIV UNIVERSITY	55 LEBANON HAIM	TEL AVIV-JAFFA		006905904		ISR	Cancer Cause and Prevention Research	000	5	5/22/2017	NON-COMPETING CONTINUATION	$199,019
														Subtotal = $199,019

Issue Date FY: 2016 ( Subtotal = $199,019 )
2016	2016	TEL AVIV UNIVERSITY	**	TEL AVIV				ISR	Cancer Cause and Prevention Research	000	4	5/23/2016	NON-COMPETING CONTINUATION	$199,019
														Subtotal = $199,019

Issue Date FY: 2015 ( Subtotal = $204,946 )
2015	2015	TEL AVIV UNIVERSITY	**	TEL AVIV				ISR	Cancer Cause and Prevention Research	000	3	5/6/2015	NON-COMPETING CONTINUATION	$204,946
														Subtotal = $204,946

Issue Date FY: 2014 ( Subtotal = $193,928 )
2014	2014	TEL AVIV UNIVERSITY	**	TEL AVIV				ISR	Cancer Cause and Prevention Research	000	2	5/30/2014	NON-COMPETING CONTINUATION	$193,928
														Subtotal = $193,928

Issue Date FY: 2013 ( Subtotal = $197,034 )
2013	2013	TEL AVIV UNIVERSITY	RAMAT-AVIV	TEL AVIV				ISR	Cancer Cause and Prevention Research	000	1	7/22/2013	NEW	$197,034
														Subtotal = $197,034

Grand Total All Awards = $986,089

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STRESS UNDERMINES IMMUNE STIMULATION: MECHANISMS & BIOLOGICAL SIGNIFICANCE

Award Number: R01CA172138

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/22/2013

PERIOD OF PERFORMANCE END DATE: 05/31/2019

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