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Combination chemo-siRNA gene therapy of nonmuscle-invading bladder cancer

Award Number: R43TR000356
ORGANIZATION: NATIONAL CENTER FOR ADVANCING TRANSLATIONAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/08/2012
PERIOD OF PERFORMANCE END DATE: 09/07/2016

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Combination chemo-siRNA gene therapy of nonmuscle-invading bladder cancer - DESCRIPTION (provided by applicant): Bladder cancer is the fourth most common cancer in the US. At presentation, >80% of bladder tumors are organ-confined, separated clinically into two groups. The most common group is the nonmuscle-invading tumors, accounting for about 70-80% of cases. This group is managed by surgery, plus neo- or adjuvant intravesical immunotherapy or chemotherapy. Intravesical therapy involves instilling a drug solution into the bladder through an indwelling catheter. Recurrence is common and occurs in 40 to 80% of patients. Between 10 to 20% of recurrences are accompanied by grade and/or stage progression (including the more fatal metastatic disease). The second group, the muscle-invading tumors, is managed by partial or complete cystectomy (removal of bladder), which presents significant risks and is not well tolerated by older patients. The most commonly used chemotherapeutic agents for intravescial therapy are mitomycin C (MMC) and doxorubicin. Through a series of preclinical and clinical studies, our group has established that their efficacy is limited by two factors: inadequate drug delivery to tumors and low chemosensitivity (especially for the more aggressive tumors). We next identified a method that uses pharmacokinetic (PK) interventions to maximize the MMC delivery to nonmuscle-invading bladder tumors. This method was tested in a multi-center, randomized phase III trial; the results confirm our hypothesis that improving the drug delivery significantly improves the 5-yr recurrence-free rate (from 23.5% to 42.6%). These data also indicate that a new approach is needed for the remaining patients who are not adequately managed by intravesical MMC therapy. Survivin is a marker/predictor of bladder cancer aggressiveness and recurrence. We have developed a pegylated cationic lipid carrier (PCat) for survivin siRNA that knockdowns the protein expression in cultured cells and in tumor-bearing animals, and enhances the antitumor activity of chemotherapy in solid tumors. Because it has been reported that inhibition of survivin enhances the sensitivity of bladder tumors to MMC, we propose to evaluate the MMC and PCat-survivin siRNA combination as an option to produce superior antitumor activity and propose to develop this combination for treating nonmuscle-invading bladder cancer. The two aims of this R43 project are to identify the optimal conditions for combining the two agents and to identify the appropriate administration route for PCat-siRNA (i.e., intravesical instillation and/or submucosal injection). PUBLIC HEALTH RELEVANCE: This R43 project has the potential to lead to a new treatment modality and significantly improve the management of bladder cancer while the disease is still localized in the bladder. Given the extremely high lifetime health care costs for these patients (over $10 billion in 2003 dollars), an additional potential benefit is cost containment.


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: 2017 ( Subtotal = $0 )
2017	2012	OPTIMUM THERAPEUTICS LLC	1815 ASTON AVE STE 107	CARLSBAD	CA	92008	SAN DIEGO	USA	National Center for Advancing Translational Sciences	000	1	2/8/2017	NEW	$0
														Subtotal = $0

Issue Date FY: 2015 ( Subtotal = $0 )
2015	2012	OPTIMUM THERAPEUTICS LLC	9363 TOWNE CENTRE DRIVE	SAN DIEGO	CA	92121	SAN DIEGO	USA	National Center for Advancing Translational Sciences	000	1	9/19/2015	NEW	$0
														Subtotal = $0

Issue Date FY: 2014 ( Subtotal = $0 )
2014	2012	OPTIMUM THERAPEUTICS LLC	9363 TOWNE CENTRE DRIVE	SAN DIEGO	CA	92121	SAN DIEGO	USA	National Center for Advancing Translational Sciences	000	1	9/17/2014	NEW	$0
														Subtotal = $0

Issue Date FY: 2012 ( Subtotal = $344,460 )
2012	2012	OPTIMUM THERAPEUTICS LLC	2287 PALMLEAF COURT	COLUMBUS	OH	43235	FRANKLIN	USA	National Center for Advancing Translational Sciences	000	1	9/8/2012	NEW	$344,460
														Subtotal = $344,460

Grand Total All Awards = $344,460

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Combination chemo-siRNA gene therapy of nonmuscle-invading bladder cancer

Award Number: R43TR000356

ORGANIZATION: NATIONAL CENTER FOR ADVANCING TRANSLATIONAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/08/2012

PERIOD OF PERFORMANCE END DATE: 09/07/2016

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