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NIVOLUMAB plus IPILIMUMAB and TEMOZOLOMIDE in combination in metastatic colorectal cancer.

ABSTRACT: Primary objectives: To evaluate the efficacy, measured as 8-month PFS rate, of the combination of TMZ, NIVO and IPI in patients achieving disease control following 2-month lead-in treatment with single agent TMZ. Primary endpoints: The primary efficacy endpoint of this study is the 8-month Progression Free Survival (PFS) rate, defined as the proportion of patients alive and progression-free.The efficacy outcome measures for this study are as follows:• Investigator-assessed PFS according to RECIST v1.1• Investigator-assessed PFS according to modified RECIST

DISEASE(S): Carcinoma Del Colon-retto Metastatico (mcrc) Con Microsatelliti Stabili (mss) Ed Mgmt Silenziato.,Colorectal Cancer,Microsatellite Stable (mss), Mgmt-silenced Metastatic Colorectal Carcinoma (mcrc).

PROVIDER: 2538691 | ecrin-mdr-crc |

REPOSITORIES: ECRIN MDR

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Project description:Glioblastoma (GBM) carries a dismal prognosis largely due to acquired resistance to the standard treatment, which incorporates the chemotherapy temozolomide (TMZ). Inhibiting the proteasomal pathway is an emerging strategy, where combination treatments are under clinical investigation. We hypothesized that pre-treatment of GBM with bortezomib (BTZ) might sensitize glioblastoma to TMZ by abolishing autophagy survival signals to augment DNA damage and apoptosis. P3 patient-derived GBM cells as well as the tumor cell lines U87, HF66, A172 and T98G were investigated for clonogenic survival after single or combined treatment with TMZ and BTZ in vitro. Change in autophagic flux was examined after experimental treatments in conjunction with inhibitors of autophagy or downregulation of autophagy-related genes -5 and -7 (ATG5 and ATG7, respectively). Autophagic flux was increased in TMZ-resistant P3 and T98G cells as indicated by diminished levels of the autophagy markers LC3A/B-II and increased STX17, higher protein degradation and no formation of p62 bodies nor induction of apoptosis. In contrast, BTZ treatment attenuated ULK1 mRNA, total and phosphorylated protein, and accumulated LC3A/B-II, p62 and autophagosomes analogously to Baf1 and chloroquine autophagy inhibitors. These autophagosomes did not fuse with lysosomes, indicated by attenuated STX17 expression and reduced degradation of long-lived proteins, which culminated in enhanced caspase-3/8 dependent apoptosis. BTZ synergistically enhanced TMZ efficacy, attenuated tumor cell proliferation, triggered ATM/Chk2 DNA damage signalling to further augment caspase-3/8 mediated apoptosis in the TMZ resistant P3 and T98G GBM cells. Genetic or chemical inhibition of autophagy (with CRISPR-CAs9 ATG5, ATG7 shRNA, MRT68921 or VPS34-IN1) abrogated BTZ efficacy and rescued BTZ+ TMZ treated GBM cells from death. We conclude that Bortezomib ameliorates temozolomide resistance through ATG5/7-dependent abrogated autophagic flux and may be amenable in combination treatment regimens for TMZ refractory GBM patients.

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NIVOLUMAB plus IPILIMUMAB and TEMOZOLOMIDE in combination in metastatic colorectal cancer.

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