Showing papers by "Michael A. Palladino published in 2012"

Phase 1 clinical trial of the novel proteasome inhibitor marizomib with the histone deacetylase inhibitor vorinostat in patients with melanoma, pancreatic and lung cancer based on in vitro assessments of the combination

Abstract: Purpose Combining proteasome and histone deacetylase (HDAC) inhibition has been seen to provide synergistic anti-tumor activity, with complementary effects on a number of signaling pathways. The novel bi-cyclic structure of marizomib with its unique proteasome inhibition, toxicology and efficacy profiles, suggested utility in combining it with an HDAC inhibitor such as vorinostat. Thus, in this study in vitro studies assessed the potential utility of combining marizomib and vorinostat, followed by a clinical trial with the objectives of assessing the recommended phase 2 dose (RP2D), pharmacokinetics (PK), pharmacodynamics (PD), safety and preliminary anti-tumor activity of the combination in patients. Experimental Design Combinations of marizomib and vorinostat were assessed in vitro. Subsequently, in a Phase 1 clinical trial patients with melanoma, pancreatic carcinoma or Non-small Cell Lung Cancer (NSCLC) were given escalating doses of weekly marizomib in combination with vorinostat 300 mg daily for 16 days in 28 day cycles. In addition to standard safety studies, proteasome inhibition and pharmacokinetics were assayed. Results Marked synergy of marizomib and vorinostat was seen in tumor cell lines derived from patients with NSCLC, melanoma and pancreatic carcinoma. In the clinical trial, 22 patients were enrolled. Increased toxicity was not seen with the combination. Co-administration did not appear to affect the PK or PD of either drug in comparison to historical data. Although no responses were demonstrated using RECIST criteria, 61% of evaluable patients demonstrated stable disease with 39% having decreases in tumor measurements. Conclusions Treatment of multiple tumor cell lines with marizomib and vorinostat resulted in a highly synergistic antitumor activity. The combination of full dose marizomib with vorinostat is tolerable in patients with safety findings consistent with either drug alone.

Synthesis and Structure−Activity Relationship Study of Antimicrotubule Agents Phenylahistin Derivatives with a Didehydropiperazine-2,5-dione Structure

Abstract: Plinabulin (11, NPI-2358) is a potent microtubule-targeting agent derived from the natural diketopiperazine “phenylahistin” (1) with a colchicine-like tubulin depolymerization activity. Compound 11 was recently developed as VDA and is now under phase II clinical trials as an anticancer drug. To develop more potent antimicrotubule and cytotoxic derivatives based on the didehydro-DKP skeleton, we performed further modification on the tert-butyl or phenyl groups of 11, and evaluated their cytotoxic and tubulin-binding activities. In the SAR study, we developed more potent derivatives 33 with 2,5-difluorophenyl and 50 with a benzophenone in place of the phenyl group. The anti-HuVEC activity of 33 and 50 exhibited a lowest effective concentration of 2 and 1 nM for microtubule depolymerization, respectively. The values of 33 and 50 were 5 and 10 times more potent than that of CA-4, respectively. These derivatives could be a valuable second-generation derivative with both vascular disrupting and cytotoxic activi...

Trypanocidal activity of β-lactone-γ-lactam proteasome inhibitors.

Abstract: Four beta-lactone-gamma-lactam proteasome inhibitors of natural origin were tested for their trypanocidal activities IN VITRO using culture-adapted bloodstream forms of TRYPANOSOMA BRUCEI. All four compounds displayed activities in the nanomolar range. The most trypanocidal compounds with 50?% growth inhibition (GI (50)) values of around 3 nM were the bromine and iodine analogues of salinosporamide A, a potent proteasome inhibitor produced by the marine actinomycete SALINISPORA TROPICA. In general, trypanosomes were more susceptible to the compounds than were human HL-60 cells. The data support the potential of beta-lactone-gamma-lactam proteasome inhibitors for rational anti-trypanosomal drug development.

synergistic cytotoxicity in multiple myeloma vivo in Combination of proteasome inhibitors bortezomib and NPI-0052 trigger

Abstract: Our recent study demonstrated that a novel proteasome inhibitor NPI-0052 triggers apoptosis in multiple myeloma (MM) cells; and importantly, is distinct from bortezomib (Velcade TM ) in its chemical structure, effects on proteasome activities, and mechanisms of action. Here, we demonstrate that combining NPI-0052 and bortezomb induces synergistic anti-MM activity both in vitro using MM cell lines or patient CD138 + MM cells and in vivo in a human plasmacytoma xenograft mouse model. NPI-0052 + bortezomib-induced synergistic apoptosis is associated with: 1) activation of caspase-8, caspase-9, caspase-3, and PARP; 2) induction of ER-stress response and JNK; 3) inhibition of migration of MM cells and angiogenesis; 4) suppression of chymotrypsin-like (CT-L), caspase-like (C-L) and trypsin-like (T-L) proteolytic activities; and 5) blockade of NF-κB signaling. Studies in a xenograft model show that low dose combination of NPI-0052 and bortezomib is well tolerated, triggers synergistic inhibition of tumor growth, and CT-L, C-L and T-L proteasome activities in tumor cells. Immununostaining of MM tumors from NPI-0052 + bortezomib-treated mice showed growth inhibition, apoptosis, and a decrease in associated angiogenesis. Taken together, our study provides the preclinical rationale for clinical protocols evaluating bortezomib together with NPI-0052 to improve patient outcome in MM. From bloodjournal.hematologylibrary.org by guest on April 12, 2012. For personal use only.