Abstract A264: Response of CNS melanoma to 4-demethyl-4-cholestrylcarbonylpenclomedine (DM-CHOC-PEN) and cell death.

Abstract

Abstract Introduction: DM-CHOC-PEN is a polychlorinated pyridine cholesteryl carbonate, which has completed a Phase I clinical trial in patients with advanced cancer - IND 68,876 (AACR 1185, 2013). DM-CHOC-PEN produced responses with improved cerebral progression free intervals (CPFI) in patients with CNS melanoma, breast, and lung cancers. CNS melanoma is of especial interest since there is no acceptable therapy for this stage of disease. DM-CHOC-PEN's principle MOA is via alkylation of DNA with N7-guanine, however, in melanoma, there is also generation of reactive oxygen species (ROS) via the DOPA/melanin pathway resulting in melanin encapsulation of melanoma cells and cell death. In mice the drug accumulated in intracerebrally/cerebellar implanted tumors, and not in normal CNS tissue, with no Purkinje cell degeneration; in contrast to drugs such as penclomedine, phencyclidine, ibogaine, etc. that also accumulate in the cerebellum but with cellular destruction. Patients with metastatic CNS cancer treated with DM-CHOC-PEN demonstrated some euphoria, but no CNS toxicity. Methods: B-16 melanoma cells were cultured in RPMI media with 5% FBS and pen/strep at 37oC in a CO2 incubator. Drugs were added to the cells during growth phase and removed after 16 hrs; responses were monitored. Adult female C57BL mice in groups of 5-6 with growing B-16 melanoma were dosed IP daily (75-200 mg/kg) for 5 days with DM-CHOC-PEN or saline and monitored daily until death or moribund and sacrificed. Animals were sacrificed, brain tumor and normal tissue removed and prepared for histology exams. Patients in the Phase I trial (DTI-021) with CNS melanoma were treated with 86.5 mg/m2 IV q 21 days and CNS lesions were monitored with MRI during the Phase I clinical trial (DTI-021) [AACR 1185, 2013]. Results: In vitro, DM-CHOC-PEN had an IC50 0.5 µg/mL against B-16 melanoma cells. Mice bearing B-16 melanoma treated with DM-CHOC-PEN (200 mg/kg/d x 5d, IP) alone vs. saline controls demonstrated %ILS of 142% - supporting the in vitro observations. Patients with CNS melanoma treated with DM-CHOC-PEN demonstrated objective responses and improved CPFI with associated melanin deposits similar to those seen with mice. DM-CHOC-PEN induced ROS via DOPA/DOPA oxidase-melanin deposits and cell death in mice with melanoma. Discussions - DM-CHOC-PEN bound to erythrocytes crosses the BBB and accumulates in CNS melanoma (not normal tissue) with intracellular DOPA-DOPA quinone and melanin formation that interrupts cancer cell metabolism and cellular death via ROS. The drug is not recycled into the systemic circulation. Electronic modeling studies support DM-CHOC-PEN's ability to act as a pyridinium co-factor in the transfer of electrons from DOPA to cytochrome c and the intermediary metabolism pool with generation of ROS. Oxidative stress and ROS generation from a DM-CHOC-PEN/DOPA-melanin pathway has now been confirmed. Cerebellar lesions appear to be especially sensitive. Conclusion: Responses and CPFI for patients with CNS cancers (and no CNS toxicity) seen in the Phase I study have been reported [AACR 1185, 2013]. The principle human toxicity was hepatic. The role for the DOPA/DOPA quinone-melanin pathway with ROS formation will be presented as a key MOA for the drug, with emphasis on cerebellar melanoma lesions. Supported in part by: NCI/ SBIR grants R43/44CA85021 and R43/44CA132257. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A264. Citation Format: Lee Roy Morgan, Edmund Benes, Andrew H. Rodgers, Roy S. Weiner, Marcus L. Ware, Philip Friedlander, Yvonne Saenger, Craig Gordon, Tallat Mahmood, Branko Jursic, Gerard Bastian. Response of CNS melanoma to 4-demethyl-4-cholestrylcarbonylpenclomedine (DM-CHOC-PEN) and cell death. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A264.