The median age was 56 years, and 9 were male. 5 individuals reported prior immuno therapy for metastatic illness, and 7 had an elevated LDH. Toxicity and clinical response Remedy with R115777 was commonly effectively tolerated. Only two patients showed grade three toxicities. 1 patient seasoned grade three nausea and vomiting, which was connected with an increased serum BUN. A second pa tient seasoned grade three myelosuppression and anorexia. These adverse events have been readily reversible. Table 1. Clinical response was assessed utilizing RECIST criteria. There have been no objective partial or comprehensive responses observed within this cohort of 14 individuals. 4 patients exhibited steady illness and went on to a second course of therapy but progressed right after an added two cycles.
All remaining individuals progressed in the course of the first cycle of remedy. Effects on farnesyltransferase enzymatic activity and chosen signaling proteins in tumor these details tissue Lack of clinical efficacy with an agent targeting a signaling pathway may be due to insufficient target inhibition, pathway modulation, or alternatively may very well be a reflection of tumor growth in spite of effective target blockade. As a way to measure directly the biological impact of R115777 on its target FT, tumor biopsies obtained just before and dur ing week 7 of remedy had been analyzed for FT enzymatic activity. Eight individuals generated tumor tissue that con tained adequate quantity and excellent of protein at each time points for analysis. As shown in Figure 1, FT enzym atic activity was suppressed by 85 98% in all tumor tissues analyzed comparing the week 7 towards the pre remedy time points.
These outcomes indicate that the target protein was inhibited quite properly in tumor tissue using the dose and schedule of R115777 made use of. Although FT inhibition could result in multiple signal ing proteins accumulating in a non farnesylated kind, if RAS itself was amongst the proteins impacted, then inhibition of downstream effectors of RAS, including ERK and Akt, could be observed. Indirect MGCD265 mechanisms to in hibit ERK and Akt activation also are conceivable. To test this notion, Western blot evaluation was performed for phospho ERK and phospho Akt in the same tumor sam ples described above. Total B actin was used as a loading handle. As shown in Figure 2, constitutive phosphoryl ation of each ERK and Akt was detected at baseline in a lot of the samples analyzed. Interestingly, in a number of samples a marked lower in detectable phospho ERK and phospho Akt was noted in the post therapy sam ples. As none of those patients skilled tumor shrinkage, these final results sug gest that important inhibition of measurable ERK and Akt activation can occur in melanoma metastases with out a demonstrable clinical response.