Abstract
In the completed phase I trial NCT01450384 combining the anti-folate pemetrexed and the multi-kinase inhibitor sorafenib it was observed that 20 of 33 patients had prolonged stable disease or tumor regression, with one complete response and multiple partial responses. The pre-clinical studies in this manuscript were designed to determine whether [pemetrexed + sorafenib] –induced cell killing could be rationally enhanced by additional signaling modulators. Multiplex assays performed on tumor material that survived and re-grew after [pemetrexed + sorafenib] exposure showed increased phosphorylation of ERBB1 and of NFκB and IκB; with reduced IκB and elevated G-CSF and KC protein levels. Inhibition of JAK1/2 downstream of the G-CSF/KC receptors did not enhance [pemetrexed + sorafenib] lethality whereas inhibition of ERBB1/2/4 using kinase inhibitory agents or siRNA knock down of ERBB1/2/3 strongly promoted killing. Inhibition of ERBB1/2/4 blocked [pemetrexed + sorafenib] stimulated NFκB activation and SOD2 expression; and expression of IκB S32A S36A significantly enhanced [pemetrexed + sorafenib] lethality. Sorafenib inhibited HSP90 and HSP70 chaperone ATPase activities and reduced the interactions of chaperones with clients including c-MYC, CDC37 and MCL-1. In vivo, a 5 day transient exposure of established mammary tumors to lapatinib or vandetanib significantly enhanced the anti-tumor effect of [pemetrexed + sorafenib], without any apparent normal tissue toxicities. Identical data to that in breast cancer were obtained in NSCLC tumors using the ERBB1/2/4 inhibitor afatinib. Our data argue that the combination of pemetrexed, sorafenib and an ERBB1/2/4 inhibitor should be explored in a new phase I trial in solid tumor patients.
Highlights
The anti-folate drug pemetrexed (Alimta®) was FDA-approved for the treatment of advanced and metastatic non-small cell lung cancer (NSCLC) in 2004
The steady state (7 day) Cmax for sorafenib is ~21 μM in plasma, with ~99% of the drug protein bound based on in vitro human serum binding assays; though it is known that the drug is rapidly taken up into tissues, and in addition patient data from clinical trials would argue that a significant amount of the drug has to be bioavailable, at least in the low micro-molar range, in a tumor based on its single agent effects by decreasing both ERK1/2 phosphorylation and reducing MCL-1 protein expression in tumor cells that are not oncogene addicted [12, 13]
As reported at the 2015 ASCO meeting, treatment of heavily pre-treated recurrent solid tumor patients with [pemetrexed + sorafenib] resulted in ~60% of all patients experiencing some degree of tumor growth delay (SD, PR, CR), with multiple partial responses and one complete response (Figure 1A; NCT01450384) [20]
Summary
The anti-folate drug pemetrexed (abbreviated in this manuscript as “PTX”) (Alimta®) was FDA-approved for the treatment of advanced and metastatic non-small cell lung cancer (NSCLC) in 2004. The steady state (7 day) Cmax for sorafenib is ~21 μM in plasma, with ~99% of the drug protein bound based on in vitro human serum binding assays; though it is known that the drug is rapidly taken up into tissues, and in addition patient data from clinical trials would argue that a significant amount of the drug has to be bioavailable, at least in the low micro-molar range, in a tumor based on its single agent effects by decreasing both ERK1/2 phosphorylation and reducing MCL-1 protein expression in tumor cells that are not oncogene addicted [12, 13]. Other studies from our groups have shown that based on the sorafenib dose the induction of ER stress may be a “protective” or a “toxic” event in the cellular response to the drug [e.g. 19]. NCT01450384 phase I trial findings in 2014, the present pre-clinical studies were initiated to define in a rational manner the most efficacious “third agent” that could enhance [pemetrexed + sorafenib] lethality
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
