CHK16 Sep 2022 16:56
Note date Aug21 Relating to Niraparab Gemcitabine
https://pubmed.ncbi.nlm.nih.gov/34503215/
Niraparib caused a significant increase in oxidative stress, and induced activation of DNA damage markers, phosphorylation of CHK2 and replication fork stalling. Importantly, niraparib, in combination with gemcitabine, produced sustained and robust inhibition of tumor growth in vivo in a patient-derived xenograft (PDX) model more effectively than either treatment alone. Furthermore, tissue samples from mice treated with niraparib and gemcitabine display significantly lower expression levels of pHH3 and Ki-67, which are a mitotic and proliferative marker, respectively. Taken together, our results indicate niraparib as a novel therapeutic agent alone or in combination with gemcitabine for CCA.
Now we have already seen reports of combination therapy of CHK1, PARP with Gemcitabine. In combination phenomenal as opposed to any two out of 3 combo.
Dec 2019 The SRA737 þ LDG (Note this relates to SCLC)
regimen mimicked the schedule currently being used in the clinical trial described above with or without anti–
PD-L1 on the third day of a weekly cycle. We did not observe a significant antitumor effect with any single agent treatments (anti–PD-L1, SRA737, or LDG), and only a moderately delayed tumor growth with combined
SRA737 and PD-L1 treatment (Fig. 4A). However, we observed remarkable tumor regressions when we combined SRA737 þ LDG with anti–PD-L1. All mice achieved some level of tumor regressions and 8 of 10 (80%) mice had complete tumor regressions which were sustained up to 60 days post treatment.
January 2019
Overall, our study revealed PARP1-mediated poly(ADP-ribosyl)ation of STAT3 as a key step in inhibiting the transcription of PD-L1, and this mechanism exists in a variety of cancer cells.
So here, I believe we have a very high probability of combo SRA 737 ( or what ever GSK choose to want to call it now), Niraparib and Gemcitabine.
iI cannot find any data on GSK that they have or have had a CHK1 inhibitor. It does not mean it does not exist or they have never had. But should they have done, then why trial with SRA737?
Sierra ( bless them) have patented 737 in combo as we know ( now owned by GSK), just before they took the for sale sign down for 737 from the window in around March 2020.
Regards