Serum TIMP-1 Levels
tumor, neuroendocrine disease, hematologic malignancies, prostate, aggressive disease, T-cell motility
DISEASE PROGRESSION, TUMOR, ADVERSE EVENTS, HEMATOLOGIC MALIGNANCIES, METASTATIC DISEASE, PROSTATE, METASTATIC PROSTATE CANCER, TUMORIGENESIS
Three responders and 4 non-responders had sufficient paired pre- and post–treatment samples available for serum TIMP-1 level testing by ELISA. Median baseline serum TIMP-1 levels were 297.5 ng/mL in the responder group and 276.0 ng/mL in the non-responders (Baseline pre-treatment serum TIMP-1 protein levels in satraplatin responders and non-responders. There is no significant difference in the medians between the 2 groups, All 3 responders demonstrated decreases in their TIMP-1 levels following the initiation of satraplatin, with a median decrease of 20.9%. One non-responder had a decrease in TIMP-1 levels after starting satraplatin, but as a group, the non-responders had a median increase of 16.1% in TIMP-1 levels (Platinum chemotherapy has definite antineoplastic activity in metastatic prostate cancer,Due to the withdrawal of support, this study of satraplatin did not meet the originally planned enrollment goal of 30 patients, which limits the analysis. The primary endpoint of PSA response rate in the evaluable cohort of patients in this study is comparable to the experience with satraplatin on the phase III SPARC trial: 31% of study patients (≥30% PSA decline) vs. 25.4% in SPARC (≥50% PSA decline) (Response to satraplatin treatment.The median time to disease progression of 5.5 weeks on study is noticeably short, especially as compared to the 11.1 weeks observed in the satraplatin arm of SPARC,As expected, responders to satraplatin had a clear advantage in time to disease progression (206 vs. 35 days, HR 0.26, 95% CI, 0.02-0.24, Incidence of most common adverse events.Additional predictive markers for platinum sensitivity outside of genomic profiling need to be developed. Peripheral blood cells are altered by their interactions with neoplastic and stromal tissue, lending clinical value to peripheral blood genomic signatures. A whole blood 6–gene RNA transcript–based signature developed by our group has been validated to have prognostic significance for overall survival in mCRPC.Differences in peripheral blood profiling among responders and non-responders can be identified and used to facilitate biomarker development. However, in this study, no clear correlation was observed between changes to the 6–gene score and response to satraplatin. This may possibly be due to the 2 tests evaluating 2 distinct biological processes. PSA change and expression are regulated by AR–dependent biochemical pathways, whereas the genes that comprise the 6–gene RNA signature (ABL2, SEMA4D, ITGAL, C1QA, TIMP-1, CDKN1A) serve immunogenic functions, playing roles in regulating T-cell motility, antigen surveillance, B-cell activation, and macrophage differentiation.Apart from the 6–gene score, increased TIMP-1 expression itself has been observed in multiple tumor types in both solid and hematologic malignancies and plays contradictory roles in tumorigenesis. It has been shown to the inhibit degradation of extracellular matrix by matrix metalloproteinases (MMPs), which modulates tumor invasion and progression of metastatic disease,Data from this study suggest that changes in serum TIMP-1 levels (measured by ELISA) may have some association with response to platinum therapy, as responders experienced an overall decrease in TIMP-1 levels, whereas non-responders had an overall increase. This is in line with previously published findings that higher levels of TIMP-1 have a greater association with neuroendocrine disease in prostate cell lines,Since DNA repair mutations are not exclusive to early-onset and histologically aggressive disease