Abstract A129: Development of turmerax therapeutic compounds in aggressive, refractory B cell non-Hodgkin's lymphoma.

Abstract

Abstract Acquired chemoresistance (ACR) is currently the most important cause of treatment failure and early mortality in DLBCL, arguably the most important but greatest unmet need in lymphoma therapy today. Diffuse Large B cell Lymphoma (DLBCL), the most common human lymphoma, comprises a genetically and clinically diverse group of aggressive B cell non-Hodgkin lymphomas (NHL-B), among a small group of important human cancers increasing in incidence in the US over the last four decades. NHL-B are the fifth most common cancers in the USA (>62,000 new cases/20,000 deaths) expected in 2011. The molecular biologic and genetic basis of the patho-physiology of these important lymphoid tumors is still mostly unresolved. Relapsed/refractory (r/rDLBCL) DLBCL is one of the most difficult scientific challenges and severe unmet therapeutic needs in clinical oncology today. This is due largely to 1.) very drug resistant tumor cells with very poor responses (<20% PR/CR) to current “salvage” therapies; and 2.) non-existent, invalid, or inadequate disease models, that we have recently been able to overcome, with development of valid chemo-refractory DLBCL a unique cell model library, derived from our patients, that now provides the opportunity to delineate critical previously unknown patho-physiologic biomarkers and in vivo molecular model mechanisms, while concurrently providing excellent models for new agent experimental therapeutics. We designed and synthesized novel inhibitors named Turmerax (TMX), when encapsulated with nano-liposomes to overcome solubility/bioavailability issues, is >1000x more effective than curcumin in inhibiting DLBCL growth and survival in vitro, and show no toxicities in normal peripheral blood lymphocytes. Liposomal-TMX (L-TMX) also targets multiple growth and survival signaling pathways, such as NF-kB and AKT, and key cellular regulatory proteins in drug resistance (MDR) in r/r DLBCL. We have also shown in vivo that L-TMX increases in survival time with decreases in lymphoma tumor burden in preliminary studies in SCID/MCL xeno-transplant (XT-SCID) models, without evidence of significant host toxicities. The development of our new agent nano-liposomal Turmerax, has provided a multi-targeted, non-toxic nano-therapeutic small molecule with the critical growth/survival (G/S) targeting specificities similar to natural product therapeutic agents (curcumin) but without the many foibles involving solubility, bioavailability, and poor in vivo potency problems, by providing a well-tolerated, well-delivered (in vivo) effective small molecule therapeutic agent, showing very promising preliminary activities on r/r DLBCL in xeno-transplant human DBLCL models, that appears to be an excellent candidate for future clinical trials. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr A129.