SBIR-STTR Award

Cancer is America's second leading cause of death. Many approved cancer drugs, such as bortezomib (Velcade), are cytotoxic agents that kill normal cells as well as tumor cells. Therapeutic benefit depends on tumor cells being more sensitive than normal cells, thereby allowing clinical responses to be achieved at relatively safe drug doses;however, damage to normal tissues is unavoidable and often limits treatment. Due to its remarkable efficacy in multiple myeloma (MM), bortezomib has been tested in solid cancers;but it has generally failed to produce clinical responses. Bortezomib inhibits an intracellular protein complex called the proteasome. Because the proteasome regulates cellular physiology in both normal and tumor cells, bortezomib causes many dose-dependent side effects of which sensory and motor dysfunction called peripheral neuropathy (PN) and deficiency in platelets (thrombocytopenia) are the most severe. MM patients can be treated safely, because MM cells can be killed by bortezomib at doses that are tolerated, albeit not without frequent incidence of PN. In contrast, tumor cells of solid cancers are more resistant, and PN and thrombocytopenia prevent administration of an effective dose of bortezomib with acceptable safety. ARI-3996 is a pro-drug version of a bortezomib-like cytotoxic agent designed to more selectively target the proteasome in solid tumors. ARI-3996 is relatively non-toxic to all cells and cannot kill tumor cells until it is activated by the enzyme, fibroblast activation protein (FAP). Because FAP is produced in epithelial tumors but not usually in healthy tissues, ARI-3996 should not be activated in nervous tissue or in bone marrow where platelets are generated. Therefore, ARI-3996 should kill FAP-producing tumors with less severe PN and thrombocytopenia than that associated with bortezomib. If successful, ARI-3996 might be combined with chemotherapy to improve the current standards of care. FAP has been shown to specifically activate ARI-3996 and unleash the bortezomib-like proteasome inhibitor to kill tumor cells in tissue culture. It is now proposed to demonstrate that ARI-3996 can kill tumors in an animal model of epithelial cancer with less systemic toxicity than bortezomib. A mouse model will be selected in which the tumor produces FAP in amounts equivalent to those in human epithelial tumors. The dose-response of ARI-3996 will be determined for reduced tumor growth, death of tumor cells, and reduced blood supply to the tumor. Mice will be examined for toxic side effects in comparison to bortezomib. For ARI-3996 to be a viable drug candidate, it will be essential to demonstrate that treatment with ARI-3996 produces significant antitumor effects with at least 10-fold less systemic toxicity than bortezomib.

Public Health Relevance:
Bortezomib (Velcade) is an effective treatment for multiple myeloma, but its mechanism of action results in dose-limiting toxicities (DLTs) of peripheral neuropathy and loss of platelets, which prevent treatment of common solid cancers. The pro-drug, ARI-3996, is designed to remain inactive in healthy organs and to be activated to unleash a cytotoxic bortezomib-like warhead in tumors by the tumor-associated enzyme called fibroblast activation protein (FAP), thereby reducing the toxic side effects that prevent safe treatment of solid tumors with bortezomib. If ARI-3996 is shown to have a bortezomib-equivalent antitumor effect in a mouse model of FAP-producing epithelial cancer with at least a 10-fold reduction in toxicity compared to bortezomib, Phase II funding for IND-enabling studies will be applied for.

Thesaurus Terms:
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Cancer is the second leading cause of death after heart disease in the US. Chemotherapy is a mainstay of treatment after surgical removal of tumors; but the balance of clinical benefit versus disabling or life- threatening side effects is often uncertain. Genotyping of cancers to identify mutated oncogenes has enabled an era of targeted therapy. Drugs targeting the mutated proteins that drive tumor growth promised to revolutionize cancer treatment; but the genetic plasticity inherent in cancer limits the numbers ofpatients who can respond to treatment, and those that do, often relapse due to development of drug resistance. This proposal describes prodrugs intended to kill tumors with reduced damage to healthy tissues. The prodrugs are designed to remain harmless until they are cleaved by the enzyme fibroblast activation protein (FAP). Short peptides are linked to cytotoxic molecules (tumor-killing warheads) to create prodrugs that only release their warheads when a specific peptide bond is cleaved enzymatically by FAP. FAP is expressed by nonmalignant fibroblasts in the connective tissue (stroma) of epithelial tumors; therefore, prodrugs enable tumors to be targeted with cytotoxic agents independently of the mutational status of the cancer cell. Prodrug feasibility was demonstrated in STTR Phase I for ARI-3996, which delivers a Velcade-like proteasome inhibitor to the tumor, and confirmed with ARI-3099DOX, which delivers the chemotherapeutic agent doxorubicin (DOX). ARI-3099DOX and ARI-3996 are both promising drug candidates. Before proceeding to IND-enabling studies, however, further work, which is planned for STTR Phase II, will be required in order to: (1) improve prodrug half-life in vivo, (2)evaluate the possible safety risk that might result from killing FAP+ cells that have recently beendiscovered in normal tissues, and (3) understand whether, by a new mechanism of action, prodrugs can relieve tumoral immune suppression to activate the immune system to kill tumors [1]. Arisaph has developed chemistry required to make prodrugs that are unique in that they are cleaved to release cytotoxic warheads by FAP, but not by a closely related enzyme, prolyl endopeptidase, which would otherwise present a major risk of toxicity to the patient because it is expressed in many healthy tissues. Developmental risk is mitigated by ability to make back up compounds, and clinical risk, by patient selection with a simple biopsy assay for FAP activity in tumor samples. Arisaph's collaborator, Dr. H. Borghaei (Fox Chase Cancer Center), has developed a model of endogenous lung cancer for testing the possible immunological effects of prodrugs. The goal of STTR Phase II is to select the most efficacious prodrug candidate, based on preclinical efficacy and safety, for IND-enabling studies that will be conducted by Arisaph in Phase III.

Thesaurus Terms:
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