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IGF-1R targeting in cancer - does sub-cellular localization matter?

ABSTRACT: The insulin-like growth factor receptor (IGF-1R) was among the most intensively pursued kinase targets in oncology. However, even after a slew of small-molecule and antibody therapeutics reached clinical trials for a range of solid tumors, the initial promise remains unfulfilled. Mechanisms of resistance to, and toxicities resulting from, IGF-1R-targeted drugs are well-catalogued, and there is general appreciation of the fact that a lack of biomarker-based patient stratification was a limitation of previous clinical trials. But no next-generation therapeutic strategies have yet successfully exploited this understanding in the clinic.Currently there is emerging interest in re-visiting IGF-1R targeted therapeutics in combination-treatment protocols with predictive biomarker-driven patient-stratification. One such biomarker that emerged from early clinical trials is the sub-cellular localization of IGF-1R. After providing some background on IGF-1R, its drugging history, and the trials that led to the termination of drug development for this target, we look more deeply into the correlation between sub-cellular localization of IGF-1R and susceptibility to various classes of IGF-1R - targeted agents.

SUBMITTER: Soni UK

PROVIDER: S-EPMC10588251 | biostudies-literature | 2023 Oct

REPOSITORIES: biostudies-literature

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IGF-1R targeting in cancer - does sub-cellular localization matter?

Soni Upendra K UK Jenny Liam L Hegde Rashmi S RS

Journal of experimental & clinical cancer research : CR 20231020 1

The insulin-like growth factor receptor (IGF-1R) was among the most intensively pursued kinase targets in oncology. However, even after a slew of small-molecule and antibody therapeutics reached clinical trials for a range of solid tumors, the initial promise remains unfulfilled. Mechanisms of resistance to, and toxicities resulting from, IGF-1R-targeted drugs are well-catalogued, and there is general appreciation of the fact that a lack of biomarker-based patient stratification was a limitation ...[more]

PMID: 37858153

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Project description:Insulin-like growth factor receptor-1 (IGF-1R) inhibition could be a relevant therapeutic approach in small cell lung cancer (SCLC) given the importance of an IGF-1R autocrine loop and its role in DNA damage repair processes. We assessed IGF-1R and pAkt protein expression in 83 SCLC human specimens. The efficacy of R1507 (a monoclonal antibody directed against IGF-1R) alone or combined with cisplatin or ionizing radiation (IR) was evaluated in H69, H146 and H526 cells in vitro and in vivo. Innovative genomic and functional approaches were conducted to analyze the molecular behavior under the different treatment conditions. A total of 53% and 37% of human specimens expressed IGF-1R and pAkt, respectively. R1507 demonstrated single agent activity in H146 and H526 cells but not in H69 cells. R1507 exhibited synergistic effects with both Cisplatin and IR in vitro. The triple combination R1507-Cisplatin-IR led to a dramatic delay in tumor growth compared to Cisplatin-IR in H526 cells. Analyzing the apparent absence of antitumoral effect of R1507 alone in vivo, we observed a transient reduction of IGF-1R staining intensity in vivo, concomitant to the activation of multiple cell surface receptors and intracellular proteins involved in proliferation, angiogenesis and survival. Finally, we identified that the nucleotide excision repair pathway (NER) was mediated after exposure to R1507-CDDP and R1507-IR in vitro and in vivo. In conclusion, adding R1507 to the current standard Cisplatin-IR doublet reveals remarkable chemo- and radiosensitizing effects in selected SCLC models and warrants to be investigated in the clinical setting. We used microarrays to investigate the effect of IGF-1R targetting on the global gene expression. Gene expression data from H526 xenografts under various treatment and time conditions Total mRNA from 33 NCI-H526 SCLC (small-cell lung cancer) xenografts was hybridized to Affymetrix HGU133 Plus 2.0 expression arrays. Log2 gene expression values were calculated using RMA. (A) To identify the molecular mechanisms involved in the response to R1507 alone along the treatment time, we performed global gene expression profiling in H526 xenografts at the following time points: baseline (vehicle), R1507 day 1 and R1507 day 7. (B) To identify the molecular mechanisms involved in the response to CDDP- and IR-R1507 combinations, we performed global gene expression profiling on mice bearing H526 xenografts treated with the following treatment conditions: vehicle, R1507 CDDP, IR, CDDP-R1507 and IR-R1507.

Dataset Information

IGF-1R targeting in cancer - does sub-cellular localization matter?

Publications

IGF-1R targeting in cancer - does sub-cellular localization matter?

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