homoharringtonine and Kidney-Neoplasms

Forty-eight previously untreated, ambulatory patients with advanced or unresectable renal carcinoma were treated with either amonafide (17 patients), caracemide (17 patients), or homoharringtonine (14 patients). No objective responses were observed in any of the treatment cohorts. Amonafide and caracemide were well tolerated with no unexpected toxicities. One patient each died of pulmonary thromboembolism and sepsis with severe metabolic acidosis on the homoharringtonine arm. An additional 4 patients experienced grade 4 complications including myelosuppression, neurologic dysfunction, and respiratory failure. These severe and unexpected complications caused early termination of accrual to the homoharringtonine arm of the study. These agents have no activity in the treatment of advanced renal cell carcinoma.

Topics: Adenine; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Renal Cell; Female; Harringtonines; Homoharringtonine; Humans; Hydroxyurea; Imides; Isoquinolines; Kidney Neoplasms; Male; Middle Aged; Naphthalimides; Organophosphonates; Survival Rate; Treatment Outcome

Renal cell carcinoma (RCC) accounts for 85% of primary renal neoplasms, and is rarely curable when metastatic. Approximately 70% of RCCs are clear-cell type (ccRCC), and in >80% the von Hippel-Lindau (VHL) gene is mutated or silenced. We developed a novel, high-content, screening strategy for the identification of small molecules that are synthetic lethal with genes mutated in cancer. In this strategy, the screen and counterscreen are conducted simultaneously by differentially labeling mutant and reconstituted isogenic tumor cell line pairs with different fluorochromes and using a highly sensitive high-throughput imaging-based platform. This approach minimizes confounding factors from sequential screening, and more accurately replicates the in vivo cancer setting where cancer cells are adjacent to normal cells. A screen of ~12,800 small molecules identified homoharringtonine (HHT), an FDA-approved drug for treating chronic myeloid leukemia, as a VHL-synthetic lethal agent in ccRCC. HHT induced apoptosis in VHL-mutant, but not VHL-reconstituted, ccRCC cells, and inhibited tumor growth in 30% of VHL-mutant patient-derived ccRCC tumorgraft lines tested. Building on a novel screening strategy and utilizing a validated RCC tumorgraft model recapitulating the genetics and drug responsiveness of human RCC, these studies identify HHT as a potential therapeutic agent for a subset of VHL-deficient ccRCCs.

Topics: Animals; Antineoplastic Agents, Phytogenic; Carcinoma, Renal Cell; Cell Line, Tumor; Drug Screening Assays, Antitumor; Female; Harringtonines; High-Throughput Screening Assays; Homoharringtonine; Humans; Kidney Neoplasms; Mice; Mice, Inbred NOD; Mice, SCID; Von Hippel-Lindau Tumor Suppressor Protein; Xenograft Model Antitumor Assays