Background:Treatment of advanced and metastatic colorectal cancer with irinotecan is hampered by severe toxicities. The active metabolite of irinotecan, SN-38, is a known substrate of drug-metabolising enzymes, including UGT1A1, as well as OATP and ABC drug transporters.Methods:Blood samples (n=127) and tumour tissue (n=30) were obtained from advanced cancer patients treated with irinotecan-based regimens for pharmacogenetic and drug level analysis and transporter expression. Clinical variables, toxicity, and outcomes data were collected.Results:SLCO1B1 521C was significantly associated with increased SN-38 exposure (P<0.001), which was additive with UGT1A1*28. ABCC5 (rs562) carriers had significantly reduced SN-38 glucuronide and APC metabolite levels. Reduced risk of neutropenia and diarrhoea was associated with ABCC2–24C/T (odds ratio (OR)=0.22, 0.06–0.85) and CES1 (rs2244613; OR=0.29, 0.09–0.89), respectively. Progression-free survival (PFS) was significantly longer in SLCO1B1 388G/G patients and reduced in ABCC2–24T/T and UGT1A1*28 carriers. Notably, higher OATP1B3 tumour expression was associated with reduced PFS.Conclusions:Clarifying the association of host genetic variation in OATP and ABC transporters to SN-38 exposure, toxicity and PFS provides rationale for personalising irinotecan-based chemotherapy. Our findings suggest that OATP polymorphisms and expression in tumour tissue may serve as important new biomarkers.
Recently protein kinases have emerged as some of the most promising drug targets; and therefore, pharmaceutical strategies have been developed to inhibit kinases in the treatment of a variety of diseases. CK2 is a serine/ threonine-protein kinase that has been implicated in a number of cellular processes, including maintenance of cell viability, protection of cells from apoptosis, and tumorigenesis. Elevated CK2 activity has been established in a number of cancers where it was shown to promote tumorigenesis via the regulation of the activity of various oncogenes and tumor suppressor proteins. Consequently the development of CK2 inhibitors has been ongoing in preclinical studies, resulting in the generation of a number of CK2-directed compounds. In the present study, an unbiased evaluation of CK2 inhibitors 4,5,6,7-tetrabromo-1H-benzotriazole (TBB), 4,5,6,7-tetrabromo-1H-benzimidazole (TBBz), and 2-dimethylamino-4,5,6,7-tetrabromo-1H-benzimidazole (DMAT) was carried out to elucidate the mechanism of action as well as inhibitor specificity of these compounds. Utilizing a chemoproteomics approach in conjunction with inhibitor-resistant mutant studies, CK2␣ and CK2␣ were identified as bona fide targets of TBB, TBBz, and DMAT in cells. However, inhibitor-specific cellular effects were observed indicating that the structurally related compounds had unique biological properties, suggesting differences in inhibitor specificity. Rescue experiments utilizing inhibitor-resistant CK2 mutants were unable to rescue the apoptosis associated with TBBz and DMAT treatment, suggesting the inhibitors had off-target effects. Exploitation of an unbiased chemoproteomics approach revealed a number of putative off-target inhibitor interactions, including the discovery of a novel TBBz and DMAT (but not TBB) target, the detoxification enzyme quinone reductase 2 (QR2). The results described in the present study provide insight into the molecular mechanism of action of the inhibitors as well as drug specificity that will assist in the development of more specific next generation CK2 inhibitors.
Neoadjuvant immunotherapy involves administering immune checkpoint inhibitors (ICIs) before surgical resection in high-risk resectable disease. This strategy was shown to have a high pathological response rate and prolonged relapse-free survival in randomized trials in melanoma, glioblastoma, and colon cancer with small numbers of patients. In resectable cancers, ICIs such as anti-programmed cell death-1 (PD1) and anti-cytotoxic T-lymphocyte-associated protein-4 (CTLA-4) can enhance anti-tumor immunity by activating antigen-specific T-cells found in the primary tumor. These tumor-reactive T-cells continue to exert anti-tumor effects on remaining neoplastic cells after the resection of the primary tumor, potentially preventing relapses from occurring. Based on the scientific rationale and early clinical observations with surrogate survival endpoints, neoadjuvant immunotherapy may provide an effective alternative to other therapeutic strategies such as adjuvant treatment. However, this can only be determined by conducting randomized controlled trials comparing neoadjuvant immunotherapy to the current standard of care for each tumor site. This review will discuss the cellular mechanisms that occur during successful neoadjuvant immunotherapy and highlight the clinical data from the available human studies that support the preclinical mechanistic data. Here we also discuss strategies required for successful neoadjuvant immunotherapy, including combination treatment strategies and resistance mechanisms to neoadjuvant treatment.
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