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Multiscale computational models for developing combination cancer therapy

Award Number: R01GM100487
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/01/2011
PERIOD OF PERFORMANCE END DATE: 06/30/2015

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Multiscale computational models for developing combination cancer therapy - DESCRIPTION (provided by applicant): Development of effective combination therapy for cancer is challenging because many cancer drugs act on intersecting signaling pathways that can interfere with each other. For example, it is well established that drug-drug interactivity can change drastically, e.g., from synergy to antagonism, depending on the treatment conditions (drug concentrations, treatment time, and sequencing of the drugs). Further, under in vivo conditions, drug concentrations change with time (i.e., pharmacokinetics or PK) and different drugs have different PK, which make it difficult to translate the findings in cultured cells where drug concentrations are typically kept constant. We propose to develop multiscale, generalizable computational PK and pharmacodynamic (PD) models to address these challenges. First, we will develop predictive in vitro PD models for single agents. These PD models employ a combination of deterministic models (that designate the fate of a single cell based on drug actions and cell cycle location) and probabilistic models (that determine the fate of all cells). These models jointly depict the response of an individual cell and the overall response of whole cell population (as the collective response of individual cells), as mathematical functions of a treatment (drug concentrations, treatment time) and chemosensitivity of a cell. Second, we will develop predictive in vitro PD models for combination therapies. Drugs can interact on two levels, i.e., cell cycle distribution (cell cycle interactivity) and molecular targets (molecular interactivity). We will extend the above approaches for single agents to develop two-drug-combination models for three types of combinations: (a) drugs with only cell cycle interactivity, (b) drugs with molecular interactivity where both drugs have cytotoxic effects, and (c) drugs with molecular interactivity where one drug does not have cytotoxicity on its own but can enhance and reduce the activity of the other drug. Third, we will develop methods to convert in vitro PD to in vivo PD. We will address two issues, i.e., conversion of CxT under in vitro conditions (constant C) to in vivo situations (changing C), and extend the in vitro PD models to include the non-cycling G0 cells present in vivo tumors. Lastly, we will integrate in vitro PD models with in vivo PK models and evaluate the performance of the integrated models. We will develop integrated PK-PD models to describe the in vivo effects of single agents, followed by models for their combinations. Model performance is evaluated in tumor-bearing animals. The proposed models are first-of-its-kind and will enable the computation of outcomes of potential combinations of different drugs and/or different in vivo treatment schedules/sequences. Such predictive models can reduce the uncertainty in outcomes and the amount of experimentation and thereby accelerate the development of effective combination cancer therapies.


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: 2019 ( Subtotal = $0 )
2019	2014	OPTIMUM THERAPEUTICS LLC	1815 ASTON AVE STE 107	CARLSBAD	CA	92008	SAN DIEGO	USA	Biomedical Research and Research Training	000	4	11/19/2018	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2017 ( Subtotal = $0 )
2017	2014	OPTIMUM THERAPEUTICS LLC	1815 ASTON AVE STE 107	CARLSBAD	CA	92008	SAN DIEGO	USA	Biomedical Research and Research Training	000	4	7/4/2017	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2016 ( Subtotal = $0 )
2016	2014	OPTIMUM THERAPEUTICS LLC	9363 TOWNE CENTRE DRIVE	SAN DIEGO	CA	92121	SAN DIEGO	USA	Biomedical Research and Research Training	000	4	7/18/2016	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2014 ( Subtotal = $337,479 )
2014	2014	OPTIMUM THERAPEUTICS LLC	9363 TOWNE CENTRE DRIVE	SAN DIEGO	CA	92121	SAN DIEGO	USA	Biomedical Research and Research Training	000	4	7/7/2014	NON-COMPETING CONTINUATION	$337,479
														Subtotal = $337,479

Issue Date FY: 2013 ( Subtotal = $325,667 )
2013	2013	OPTIMUM THERAPEUTICS LLC	2287 PALMLEAF COURT	COLUMBUS	OH	43235	FRANKLIN	USA	Biomedical Research and Research Training	000	3	7/1/2013	NON-COMPETING CONTINUATION	$325,667
														Subtotal = $325,667

Issue Date FY: 2012 ( Subtotal = $337,479 )
2012	2012	OPTIMUM THERAPEUTICS LLC	2287 PALMLEAF COURT	COLUMBUS	OH	43235	FRANKLIN	USA	Biomedical Research and Research Training	000	2	8/2/2012	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$337,479
														Subtotal = $337,479

Issue Date FY: 2011 ( Subtotal = $286,700 )
2011	2011	OHIO STATE UNIVERSITY	1800 CANNON DR/700 LINCOLN TOW	COLUMBUS	OH	43210	FRANKLIN	USA	Biomedical Research and Research Training	000	1	8/22/2011	NEW	$286,700
														Subtotal = $286,700

Grand Total All Awards = $1,287,325

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Multiscale computational models for developing combination cancer therapy

Award Number: R01GM100487

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/01/2011

PERIOD OF PERFORMANCE END DATE: 06/30/2015

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