IGF-1R and mTOR Blockade: Novel Resistance Mechanisms and Synergistic Drug Combinations for Ewing Sarcoma

Lamhamedi-Cherradi, Salah-Eddine; Menegaz, Brian A.; Ramamoorthy, Vandhana; Vishwamitra, Deeksha; Wang, Ying; Maywald, Rebecca L.; Buford, Adriana S.; Fokt, Izabela; Skóra, Stanisław; Wang, Jing; Naing, Aung; Lazar, Alexander J.; Rohren, Eric M.; Daw, Najat C.; Subbiah, Vivek; Benjamin, Robert S.; Ratan, Ravin; Priebe, Waldemar; Mikos, Antonios G.; Amin, Hesham M.; Ludwig, Joseph A.

doi:10.1093/jnci/djw182

Cited by 49 publications

(38 citation statements)

References 44 publications

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“…This effect was accompanied with a partial and durable inhibition of phospho‐S6 and a transient inhibition of phospho‐AKT (S473) which recovered pretreatment levels after 24 hr. Several mechanisms of resistance involving the recovering of PI3K/AKT signaling after the activation of mTORC2 via IGFR1 or PDGFR signaling have been described for different mTOR inhibitors . Therefore, the restoring of AKT signaling may be in the basis of the resistance to the treatment with EC‐70124.…”

Section: Discussionmentioning

confidence: 99%

“…Several mechanisms of resistance involving the recovering of PI3K/AKT signaling after the activation of mTORC2 via IGFR1 or PDGFR signaling have been described for different mTOR inhibitors. 20,22,23 Therefore, the restoring of AKT signaling may be in the basis of the resistance to the treatment with EC-70124. Nevertheless, we have not detected an increased phosphorilation of IGF1R or PDGFR after EC-70124-treatment in vitro (Supporting Information Fig.…”

Section: Discussionmentioning

confidence: 99%

“…Clinical testing of rapamycin and its derived analogs has provided at best only modest results . This limited response may be explained by the fact that these compounds are efficient inhibitors of mTORC1 but not mTORC2 which contribute to induce an adaptive resistance due to the reactivation of AKT . Therefore, a new generation of inhibitors able to target both complexes and/or combinatorial strategies aimed to prevent resistance to mTOR inhibitors are being tested in sarcomas …”

Section: Introductionmentioning

confidence: 99%

“…21 This limited response may be explained by the fact that these compounds are efficient inhibitors of mTORC1 but not mTORC2 which contribute to induce an adaptive resistance due to the reactivation of AKT. 22 Therefore, a new generation of inhibitors able to target both complexes and/or combinatorial strategies aimed to prevent resistance to mTOR inhibitors are being tested in sarcomas. [22][23][24] Targeting several key oncogenic signals with a single agent may constitute an ideal alternative to increase efficiency and prevent the activation of resistance mechanisms.…”

Section: Introductionmentioning

confidence: 99%

“…22 Therefore, a new generation of inhibitors able to target both complexes and/or combinatorial strategies aimed to prevent resistance to mTOR inhibitors are being tested in sarcomas. [22][23][24] Targeting several key oncogenic signals with a single agent may constitute an ideal alternative to increase efficiency and prevent the activation of resistance mechanisms. In line with this aim, EC-70124 is a hybrid indolocarbazole analog 25 with a potent multikinase inhibitor spectrum affecting key signaling kinases implicated in pro-survival and proliferative pathways.…”

Section: Introductionmentioning

confidence: 99%

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The multikinase inhibitor EC‐70124 synergistically increased the antitumor activity of doxorubicin in sarcomas

Estupiñán

Santos

Rodríguez

et al. 2019

Intl Journal of Cancer

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Cytotoxic drugs like doxorubicin remain as the most utilized agents in sarcoma treatment. However, advanced sarcomas are often resistant, thus stressing the need for new therapies aimed to overcome this resistance. Multikinase inhibitors provide an efficient way to target several pro‐tumorigenic pathways using a single agent and may constitute a valuable strategy in the treatment of sarcomas, which frequently show an aberrant activation of pro‐tumoral kinases. Therefore, we studied the antitumor activity of EC‐70124, an indolocarbazole analog that have demonstrated a robust ability to inhibit a wide range of pro‐survival kinases. Evaluation of the phospho‐kinase profile in cell‐of‐origin sarcoma models and/or sarcoma primary cell lines evidenced that PI3K/AKT/mTOR, JAK/STAT or SRC were among the most highly activated pathways. In striking contrast with the structurally related drug midostaurin, EC‐70124 efficiently prevented the phosphorylation of these targets and robustly inhibited proliferation through a mechanism associated to the induction of DNA damage, cell cycle arrest and apoptosis. In addition, EC‐70124 was able to partially reduce tumor growth in vivo. Importantly, this compound inhibited the expression and activity of ABC efflux pumps involved in drug resistance. In line with this ability, we found that the combined treatment of EC‐70124 with doxorubicin resulted in a synergistic cytotoxic effect in vitro and an increased antitumor activity of this cytotoxic drug in vivo. Altogether, these results uncover the capability of the novel multikinase inhibitor EC‐70124 to counteract drug resistance in sarcoma and highlight its therapeutic potential when combined with current treatments.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The multikinase inhibitor EC‐70124 synergistically increased the antitumor activity of doxorubicin in sarcomas

Estupiñán

Santos

Rodríguez

et al. 2019

Intl Journal of Cancer

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Costs and Causes of Oncology Drug Attrition With the Example of Insulin-Like Growth Factor-1 Receptor Inhibitors

Jentzsch,

Osipenko,

Scannell

et al. 2023

JAMA Netw Open

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ImportanceThe development of oncology drugs is expensive and beset by a high attrition rate. Analysis of the costs and causes of translational failure may help to reduce attrition and permit the more appropriate use of resources to reduce mortality from cancer.ObjectiveTo analyze the causes of failure and expenses incurred in clinical trials of novel oncology drugs, with the example of insulin-like growth factor-1 receptor (IGF-1R) inhibitors, none of which was approved for use in oncology practice.Design, Setting, and ParticipantsIn this cross-sectional study, inhibitors of the IGF-1R and their clinical trials for use in oncology practice between January 1, 2000, and July 31, 2021, were identified by searching PubMed and ClinicalTrials.gov. A proprietary commercial database was interrogated to provide expenses incurred in these trials. If data were not available, estimates were made of expenses using mean values from the proprietary database. A search revealed studies of the effects of IGF-1R inhibitors in preclinical in vivo assays, permitting calculation of the percentage of tumor growth inhibition. Archival data on the clinical trials of IGF-1R inhibitors and proprietary estimates of their expenses were examined, together with an analysis of preclinical data on IGF-1R inhibitors obtained from the published literature.Main Outcomes and MeasuresExpenses associated with research and development of IGF-1R inhibitors.ResultsSixteen inhibitors of IGF-1R studied in 183 clinical trials were found. None of the trials, in a wide range of tumor types, showed efficacy permitting drug approval. More than 12 000 patients entered trials of IGF-1R inhibitors in oncology indications in 2003 to 2021. These trials incurred aggregate research and development expenses estimated at between $1.6 billion and $2.3 billion. Analysis of the results of preclinical in vivo assays of IGF-1R inhibitors that supported subsequent clinical investigations showed mixed activity and protocols that poorly reflected the treatment of advanced metastatic tumors in humans.Conclusions and RelevanceFailed drug development in oncology incurs substantial expense. At an industry level, an estimated $50 billion to $60 billion is spent annually on failed oncology trials. Improved target validation and more appropriate preclinical models are required to reduce attrition, with more attention to decision-making before launching clinical trials. A more appropriate use of resources may better reduce cancer mortality.

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Role of tumor microenvironment in cancer progression and therapeutic strategy

et al. 2023

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Cancer is now considered a tumor microenvironment (TME) disease, although it was originally thought to be a cell and gene expression disorder. Over the past 20 years, significant advances have been made in understanding the complexity of the TME and its impact on responses to various anticancer therapies, including immunotherapies. Cancer immunotherapy can recognize and kill cancer cells by regulating the body's immune system. It has achieved good therapeutic effects in various solid tumors and hematological malignancies. Recently, blocking of programmed death‐1 (PD‐1), programmed death‐1 ligand‐1 (PD‐L1), and programmed death Ligand‐2 (PD‐L2), the construction of antigen chimeric T cells (CAR‐T) and tumor vaccines have become popular immunotherapies Tumorigenesis, progression, and metastasis are closely related to TME. Therefore, we review the characteristics of various cells and molecules in the TME, the interaction between PD‐1 and TME, and promising cancer immunotherapy therapeutics.

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IGF-1R and mTOR Blockade: Novel Resistance Mechanisms and Synergistic Drug Combinations for Ewing Sarcoma

Abstract: We discovered new druggable targets expressed by chemoresistant ES cells, xenografts, and relapsed human tumors. Joint suppression of these newfound targets, in concert with IGF-1R or mTOR blockade, should improve clinical outcomes.

Cited by 49 publications

References 44 publications

The multikinase inhibitor EC‐70124 synergistically increased the antitumor activity of doxorubicin in sarcomas

The multikinase inhibitor EC‐70124 synergistically increased the antitumor activity of doxorubicin in sarcomas

Costs and Causes of Oncology Drug Attrition With the Example of Insulin-Like Growth Factor-1 Receptor Inhibitors

Role of tumor microenvironment in cancer progression and therapeutic strategy

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