In the previous funding period, based on the hypothesis that maintenance of telomere function is critical toMM cell survival, we investigated the mechanisms maintaining telomere function in MM and evaluatedinhibitors of telomerase/telomeres as novel therapeutics. We have shown that telomerase activity isincreased, while telomere length is shorter, in MM cells and cell lines compared to normal plasma cells,providing a critical therapeutic index for using telomere maintenance mechanism-directed novel therapeutics.We have further evaluated the mechanisms regulating telomerase activity in MM. Specifically, we haveidentified that the important MM survival signals are also mechanisms maintaining telomerase activity. Wehave demonstrated that IL-6 and IGF-1, which induce MM cell proliferation and survival, also increasetelomerase activity; these cytokines augment telomerase activity through NFkB-mediated upregulation ofboth hTERT mRNA and protein expression; as well as through Akt-mediated hTERT phosphorylation andactivation. We have also gone on to show that hsp90 complexes with and modulates telomerase activity;conversely, inhibition of hsp90 by 17-AAG leads to inhibition of telomerase activity. Finally, we haveevaluated the effects of various inhibitors of telomerase in MM and identified efficacy of GRN163L, anantisense lipidated oligonucleotide hTERT inhibitor, both in vitro as well as in vivo in a murine model ofhuman MM. In this renewal application, we are initiating a phase I study of GRN163L in relapsed andrelapsed refractory MM, we will evaluate the clinical and molecular effects of GRN163L in myeloma; as wellas identify agents that are synergistic with telomerase inhibition in preclinical in vitro and in vivo models. Themolecular correlates of response versus resistance identified in the single agent clinical study, coupled withpreclinical identification of combinations with synergistic anti-MM activity, will provide the framework forcombination clinical trials. To this end, the following aims will be pursued:
Specific Aim 1 : To investigatesafety, efficacy, and molecular correlates of telomerase-targeting GRN163L therapy in patients with relapsedor refractory MM;
Specific Aim 2 : To define rationally-based combinations of telomerase inhibitor and novelagents which mediate synergistic MM cytotoxicity in vitro;
and Specific Aim 3 : To define the in vivo efficacyof telomerase inhibitor combination therapies in murine models of human MM for translation to derivedclinical studies.
Showing the most recent 10 out of 407 publications
