Abstract. Prostate cancer (PCa) is the most common malignancy and the second leading cause of cancer death in men in the United States. Although surgery and radiation therapy in patients with low risk disease appear appropriate and effective, those with high-risk localized disease almost always become hormone refractory and then rapidly progress. New treatment strategy is urgently needed for patients with high-risk localized prostate cancer, particularly an approach that considers the use of a multimodal approach and that includes both local and systemic therapies. Cytotoxic drugs are broadly used to treat hematological malignancies and solid tumors and, under certain clinical conditions, have changed the natural course of some of these diseases. While effective, due to their intrinsic mode of action, they may also cause significant off-target adverse events that could preclude their full clinical efficacy, possibly resulting in early discontinuation of medication and a consequent increased risk of tumor relapse or recurrence. Alternative approaches to both maintain the effectiveness of chemotherapeutic drugs and minimize systemic toxicity include conjugation of cytotoxic agents to humanized antibodies (also known as Antibody Drug Conjugates, ADCs). The durable clinical responses reported with brentuximab vedotin (SGN-35: Seattle Genetics/Takeda) and trastuzumab emtansine (T-DM1; Roche in partnership with ImmunoGen), which have recently obtained regulatory approval, have profoundly changed the outlook for ADC cancer therapy. These approaches, although showing strong potential, are extremely expensive, and less complex and more cost-efficient methodologies are needed. Here we describe the use of a novel ligand for prostate specific membrane antigen (PSMA, a biomarker for prostate cancer) to target a potent microtubule inhibiting agent, MMAE, and a photodynamic therapy (PDT) agent, IR700, selectively to prostate cancers. The design of this new drug molecule utilizes a prodrug approach and simultaneously delivers two drugs selectively to prostate cancer. By selective delivery of two drugs with different therapeutic mechanisms to cancer cells, improved antitumor activity with less toxicity is expected. The reduction in toxicity is expected due to anticipated drug synergy (requiring lower drug doses), site specific prodrug activation, and rapid clearance of the drug molecule, preventing off target delivery. This molecule will be developed using two animal models of prostate cancer, heterotopic human prostate cancer in mice and spontaneous prostate cancer in companion dogs. Both MMAE and IR700 therapy have been noted to stimulate immune response against cancer and we will preliminarily tested this in the immunocompetent companion dogs. Dog pathology and physiology of prostate cancer is very similar to humans and dogs are often used in drug development trials. Since efficacy trials in mice are not predictive of human results, efficacy studies in dogs will substantially encourage clinical translation of the developed agent.

Narrative The proposed methods will develop a PSMA-targeted therapeutic agent that combines chemotherapy and photodynamic therapy for the treatment of prostate cancer, optimize it in small animal models of prostate cancer, and then obtain toxicity and efficacy data in a large animal model, dogs. Dogs spontaneously develop prostate cancer that closely replicates the disease pathology and progression in humans. The agent is fluorescent as well as a therapeutic allowing for a theranostic approach in small animals that will decrease the time for molecule optimization; future clinical translation of the technology will have the potential to impact prostate cancer therapy.