Although oxaliplatin is a third-generation platinum drug, it has become the most prescribed amongst all platinum drugs overtaking its predecessors, cisplatin and carboplatin. To date, oxaliplatin has become an integral part of various chemotherapy protocols, especially in advanced colorectal cancer. For colorectal cancer, oxaliplatin has been used with folinic acid (leucovorin) and 5-flurouracil (5-FU);this combination, referred to as FOLFOX, is now a treatment standard for colorectal cancer. Unfortunately, like many other anticancer drugs, oxaliplatin has several significant side effects, most notably, thrombocytopenia. The use FOLFOX is well established and widely used for colorectal cancer. However, thrombocytopenia has been noted in more than 70% of patients receiving FOLFOX. As of today, there is no FDA approved drug indicated specifically for treating oxaliplatin-induced thrombocytopenia. Therefore, it is of great importance to develop a new agent specifically for oxaliplatin-induced thrombocytopenia. The ultimate goal of this project is t develop a novel small-molecule TNF- modulator, UTL-5g, to be used in conjunction with oxaliplatin for the treatment of colon cancer to significantly reduce oxaliplatin-induced thrombocytopenia. In this SBIR phase I study, several preclinical studies will be conducted to achieve the following specific aims:
Aim 1. To show that, in a dose dependent manner, UTL-5g increases number of platelets lowered by oxaliplatin in vivo (a) To determine the nadir of platelet count after oxaliplatin treatment at the MTD (i.e., how many days after oxaliplatin treatment will platelet level be the lowest?). (b) To define the relationship of dose/schedule of UTL-5g and blood platelet counts. (c) To blend the schedule and doses obtained from (a) and (b) to show the effectiveness of UTL-5g in ameliorating the platelet suppression induced by oxaliplatin. For all these studies, when applicable, we will conduct counts/analyses on platelets, WBC, bone marrow and CD41+ megakaryocytes. We will also monitor the injuries on liver and kidney by analyzing AST, ALT, BUN, and creatine. In addition, cytokines, including TNF- and IL-10 (both are significantly reduced by oxaliplatin) will be assayed.
Aim 2. Based on aim 1, to select a dose range and conduct a therapeutic assessment to show that UTL-5g does not affect the anticancer activity of oxaliplatin (using a human colorectal cell line, HCT-15). Once this SBIR Phase I study is successfully completed, we will have shown the feasibility that UTL-5g can be used in conjunction with oxaliplatin to relieve oxaliplatin-induced thrombocytopenia and UTL-5g is a promising adjuvant agent worthy of continued preclinical development.
The ultimate goal of this project is to develop a novel small-molecule TNF- modulator, UTL-5g, to be used in conjunction with oxaliplatin for the treatment of colon cancer to significantly reduc oxaliplatin-induced thrombocytopenia.
|Carruthers, Nicholas J; Stemmer, Paul M; Chen, Ben et al. (2017) Phosphoproteome and transcription factor activity profiling identify actions of the anti-inflammatory agent UTL-5g in LPS stimulated RAW 264.7 cells including disrupting actin remodeling and STAT-3 activation. Eur J Pharmacol 811:66-73|