SBIR-STTR Award

Strong evidence supports the notion that chemoprevention has the potential to be a major component of colorectal cancer control. The prevention of cancer depends heavily on the development of safe and effective agents. NSAIDs prevent colorectal cancer but have two major limitations that preclude their large-scale application to prevent colorectal cancer: a) significant side effects, accounting per year for >15,000 deaths in the US; and b) limited efficacy, which, at best, is below 50%. A significant development in the prevention of colon cancer is the combined use of sulindac and difluoromethylornithine (DFMO); sulindac stimulates polyamine acetylation and export from the cell and DFMO inhibits the enzyme ornithine decarboxylase, which catalyzes the rate-limiting step in polyamine synthesis. The end result is reduced polyamine levels leading to suppressed growth of cancer cells. We have synthesized MDC-1231, a novel compound that a) when combined with DFMO prevents nearly completely colon cancer in preclinical models, and b) appears safe. Our hypothesis is that MDC-1231 is a safe and, when combined with DFMO, highly effective chemopreventive agent against colon cancer. To evaluate this hypothesis, we propose the following specific aims: 1) Determine the chemoprevention efficacy of MDC-1231 plus DFMO in human colon cancer xenografts in nude mice; 2) Perform toxicity studies of MDC-1231 combined with DFMO; and 3) Study the metabolism, pharmacokinetics and pharmacodynamics of MDC-1231. These aims will assess parameters that are essential to the development of MDC-1231. The results of the proposed studies will pave the way towards the completion of the preclinical development of MDC-1231 ultimately leading to a phase I clinical trial.

Public Health Relevance:
The anti-inflammatory drug sulindac combined with another compound (DFMO) prevents colon cancer. Sulindac, however, has significant side effects especially when given for prolonged periods of time. MDC-1123 is a novel sulindac-like drug that in preclinical studies appears safer and very effective in the prevention of colon cancer. The impact of this work on public health will be significant, as it will contribute to the development of an effective strategy for the control of colon cancer.

Thesaurus Terms:
"(Z)-5-Fluoro-2-Methyl-1-[[4-(Methylsulfinyl)Phenyl]methylene]-1h-Indene-3-Acetic Acid; 2-(Difluoromethyl)-Dl-Ornithine; Abnormal Assessment Of Metabolism; Accounting; Acetylation; Adverse Effects; Anti-Inflammatories; Anti-Inflammatory Agents; Anti-Inflammatory; Antiinflammatories; Antiinflammatory Agents; Athymic Nude Mouse; Blood Plasma; Cancer Cell Growth; Cancer Control; Cancer Control Science; Cancers; Cells; Cessation Of Life; Chemoprevention; Chemopreventive; Chemopreventive Agent; Clinical Trials; Clinical Trials, Phase I; Clinical Trials, Unspecified; Colon Cancer; Colon Carcinoma; Colonic Carcinoma; Colorectal Cancer; Dfmo; Dl-Alpha-Difluoromethylornithine; Death; Development; Drug Kinetics; Drug Toxicity; Drugs; Early-Stage Clinical Trials; Eflornithine (Dfmo Ornidyl); Enzymes; Exanthem; Exanthema; Figs; Figs - Dietary; Hepatic; Heterograft; Human; Human, General; Individual; Itching; Kidney; L-Ornithine Carboxy-Lyase; Life; Malignant Neoplasms; Malignant Tumor; Man (Taxonomy); Man, Modern; Medication; Metabolic Studies; Metabolism Studies; Mice, Athymic; Mice, Nude; Molecular Target; Nude Mice; Odc; Ornithine Carboxy-Lyase; Ornithine Decarboxylase; Patients; Pharmaceutic Preparations; Pharmaceutical Preparations; Pharmacodynamics; Pharmacokinetics; Phase 1 Clinical Trials; Phase I Clinical Trials; Phase I Study; Plasma; Polyamine Compound; Polyamines; Pre-Clinical Model; Preclinical Models; Prevention; Pruritic Disorder; Pruritis; Pruritus; Public Health; Rash; Recurrence; Recurrent; Reticuloendothelial System, Serum, Plasma; Safety; Seminal; Serum, Plasma; Skin Rash; Sulindac; Time; Toxic Effect; Toxicities; Transplantation, Heterologous; Treatment Side Effects; Urinary System, Kidney; Western World; Work; Xenograft; Xenograft Procedure; Xenotransplantation; Adenoma; Anticarcinogenic; Cancer Prevention; Chemotherapy; Cis-5-Fluoro-2-Methyl-1-[p-(Methylsulfinyl)Benzylidene]indene-3-Acetic Acid; Clinical Investigation; Difluoromethylornithine; Drug Efficacy; Drug Metabolism; Drug/Agent; Gastrointestinal; Malignancy; Metabolic Abnormality Assessment; Neoplasm/Cancer; Novel; Phase 1 Study; Phase 1 Trial; Phase I Trial; Pre-Clinical; Preclinical; Preclinical Evaluation; Preclinical Study; Prevent; Preventing; Protocol, Phase I; Public Health Medicine (Field); Public Health Relevance; Renal; Side Effect; Therapy Adverse Effect; Treatment Adverse Effect"

The chemoprevention of colon cancer has been hampered by either weak agents or significant side effects. It was recently shown that the combination of sulindac with difluoromethylornithine (DFMO) prevents nearly 70% of colon cancer, assessed as colon polyp recurrence. Sulindac, however, has frequent and significant side-effects that make its long-term application to cancer prevention problematic. Our phase I STTR assessed the potential role of our sulindac-like compound MDC-1231, also known as phosphosulindac (PS), in colon cancer prevention. PS has increased potency and safety compared to sulindac and acts synergistically with DFMO to prevent colon cancer with an efficacy of 91%. Our goal is to replace sulindac with PS in the successful combination with DFMO in order to develop a superior approach to colon cancer prevention. We have accomplished all the goals of the phase I grant. The goal of the present phase II application is to complete the preclinical development of PS and submit an FDA IND application. We propose five specific aims, some of them will be pursued in parallel and influence each other. Specific Aim #1: Complete the studies on the metabolism;perform PK/PD and biodistribution of the optimized oral formulation of PS. Specific Aim #2: Scale up the synthesis of PS under GMP conditions. Specific Aim #3: Develop an oral formulation of PS and determine its stability. Specific Aim #4: Perform toxicity studies of PS;they include animal toxicity and genotoxicity studies. Specific Aim #5: Prepare an IND protocol and package for FDA submission. The proposed work, if successful, will contribute greatly towards a realistic strategy for human colon cancer chemoprevention.

Public Health Relevance:
Colon cancer is a major cause of cancer deaths in the US and worldwide. The prevention of colon cancer using pharmacological agents is now a realistic possibility, but new agents are urgently needed. We are proposing to develop a novel compound, phospho-sulindac, which is potentially a highly effective and safe chemopreventive agent. The expected results will pave the way towards the completion of phospho-sulindac's preclinical evaluation, a required step prior to its testing in humans.