Highly selective targeted theranostics for prostate cancers

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.

Grant Number: 5R01CA255925-04
NIH Institute/Center: NIH
Principal Investigator: James Basilion