Investigation of a nanoparticle albumin-bound mTOR inhibitor, nab-rapamycin for t

DESCRIPTION provided by applicant In it is estimated that there will be new bladder cancer cases in the United States resulting in deaths Most cases present with nonmuscle invasive bladder cancer NMIBC Intravesical bacillus Calmette Guerin BCG which elicits a nonspecific local immune response is considered the standard first line treatment However over of NMIBC will recur Several chemotherapeutics have been explored in the second line setting with only limited efficacy forcing many patients into a radical cystectomy Because of high disease recurrence and morbidity the cost per bladder cancer patient is among the highest of all cancers Thus the development of an effective molecularly targeted intravesical therapy is highly desirable Inhibition of the mTOR signaling pathway is a promising therapy for bladder cancer In a genetically engineered mouse bladder cancer model that recapitulates the human disease developed by our collaborators at Columbia University mTOR expression increased with disease progression and the mTOR inhibitor rapamycin effectively prevented tumor progression when administered intravesically Furthermore rapamycin was found to potentiate the induction of a BCG mediated immune response in mice Thus we believe that intravesical therapy with rapamycin may have significant therapeutic value in the treatment of NMIBC as a rational molecularly targeted therapy A novel injectable nanoparticle albumin bound rapamycin was developed nab rapamycin and in various xenograft tumor models nab rapamycin decreased downstream signaling and showed excellent efficacy In a phase clinical study intravenous nab rapamycin was safe with evidence of responses and stable disease in a variety of solid tumors internal data nab rapamycin is in the process of being licensed to AADi LLC a start up company which is the applicant for this grant We propose to conduct a combined phase clinical trial to assess safety toxicity and efficacy of local intravesical administration of nab rapamycin in patients with NMIBC that have failed BCG treatment Our specific aims are Phase I portion in a clinical phase study establish safety and maximum tolerated dose of intravesical nab rapamycin in a genetically engineered mouse bladder cancer model evaluate efficacy of the combination of intravesical nab rapamycin and BCG Phase II portion in patients evaluate blood and bladder tissue levels of nab rapamycin evaluate potential predictive clinical biomarkers evaluate efficacy safety in a clinical phase study of single agent nab rapamycin and evaluate efficacy safety in a phase combination with BCG This proposal will present a unique opportunity to develop the first targeted molecular therapy with nab rapamycin for intravesical treatment of bladder cancer Our ultimate goal is to seek FDA approval With approximately new bladder cancer cases in the United States and almost deaths every year and because of high disease recurrence and morbidity the cost per bladder cancer patient is among the highest of all cancers Non muscle invasive bladder cancer NMIBC is a recurrent disease and an effective molecularly targeted intravesical therapy especially after failure of first line therapy is highly desirable as there are not proven effective options for patients in this setting The relevance of this proposal lies in its potential to provide better outcomes in patients with NMIBC that have failed standard therapies