Combination with Immuno-Oncology Agents
Numerous researchers have demonstrated the importance of the tumor immune microenvironment in determining an individual patient’s response to immunotherapy regimens. Euclises is studying the impact of ECP-1014 on disabling or reprogramming these immunosuppressive microenvironments that can drive non-responsiveness to immuno-oncology drugs.
Overproduction of prostaglandin E2 (PGE-2) by COX-2 promotes tumor proliferation, invasiveness, metastasis, and, most importantly for Euclises’ therapies, suppression of the immune system. PGE-2 mediated immune suppression in the TME has been suggested as the root of non-responsiveness to IO agents in certain tumors types and patients. These effects are especially pronounced in tumor types in which the COX-2 enzyme is known to be over-expressed or highly active.
In addition, animal tumor models show that ECP-1014 can quite effectively convert “cold” tumors (those that are typically non-responsive to checkpoint therapy) into “hot” tumors with dramatic immune responses. Combination with checkpoint inhibitors in these tumor lines has resulted in regression and even complete eradication of the tumor. These findings underscore the potential for Euclises’ drugs to work synergistically with IO agents and to transform patient outcomes particularly in the context of COX-2 dependent tumors that have historically shown poor response to IO therapy.
Combination with EGFR Inhibitors
Epidermal growth factor receptor (EGFR) overexpression causes uncontrolled cell division and tumor proliferation in many cancers, and EGFR inhibitors often have an initial 60% response rate in patients, higher than conventional chemotherapy. Unfortunately, in too many patients, these responses fail and their cancer resumes its progress within months. Euclises is studying the impact of ECP-1014 on both increasing initial response to EGFR inhibitors, and blocking this rapid development of resistance to EGFR therapy.
Research suggests that EGFR and COX-2 pathways are interlocked in complex ways which may exacerbate the effects of PGE-2 on tumor metastasis and invasion and of EGFR on proliferation. Activation of EGFR results in enhanced expression of COX-2 and increased synthesis of prostaglandins  which causes resistance to EGFR inhibition therapies  through downregulation of E-cadherin  and activation of mitrogen activated protein kinase (MAPK)/extracellular signal regulated kinase (Erk) [2,3].
As a single agent, Euclises’ lead candidate has shown promising anti-cancer activity against high COX-2 activity cancers both in vitro and in animal models. Combination with EGFR inhibitors has been even more effective, and Euclises is studying whether EGFR inhibition may in fact make other cancer cell lines responsive to ECP1014.
Some prior clinical trials have shown a dramatic increase in both progression-free and overall survival with the addition of COX-2 blockade to EGFR inhibitors in patients with elevated tumor PGE-2. ECP-1014 is both more potent and more selective than older COX-2 inhibitors, and thus effective patient selection in the clinic will unlock this powerful anti-cancer synergy in combination with EGFR inhibitors. – Clin Cancer Res 2005;6099 11(17)  – Cancer. 2015 Sep 15;121(18):3298-306.  – Cancer Res. 2005;65:6275-6281.