A phase I pilot study of the insulin-like growth factor 1 receptor pathway modulator AXL1717 in combination with gemcitabine HCl and carboplatin in previously untreated, locally advanced, or metastatic non-small cell lung cancer

Holgersson, Georg; Bergström, Stefan; Harmenberg, Johan; Ringbom, Magnus; Klockare, Maria; Jerling, Markus; Ekman, Simon; Lundström, Kristina Lamberg; Koyi, Hirsh; Brandén, Eva; Larsson, Olle; Bergqvist, Michael

doi:10.1007/s12032-015-0578-y

Cited by 13 publications

(8 citation statements)

References 14 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The practical feasibility of combination ALK/IGF-1R inhibition as a clinical strategy has been given a boost by recent research into the IGF-1R inhibitor AXL1717 in advanced non-small cell lung cancer. Early results have indicated that as a monotherapy AX1717 is as effective as existing chemotherapy and with less toxicity 22 – 24 . Moreover, the role of IGF-1R activation in non-small lung cancer prognosis has been very recently confirmed in a study of 326 NSCLC patients 25 .…”

Section: Discussionmentioning

confidence: 99%

ALK and IGF-1R as independent targets in crizotinib resistant lung cancer

Wilson

Nimick

Nehoff

et al. 2017

Sci Rep

View full text Add to dashboard Cite

ALK positive non-small cell lung cancer is highly responsive to ALK inhibitors such as crizotinib, but drug resistance typically develops within a year of treatment. In this study we investigated whether IGF-1R is an independent druggable target in ALK-positive lung cancer cells. We confirmed that combination ALK and IGF-1R inhibitor treatment is synergistically cytotoxic to ALK-positive lung cancer cells and that this remains the case for at least 12 days after initial exposure to crizotinib. ALK-positive cells with acquired resistance to crizotinib did not acquire cross-resistance to IGF-1R inhibition, though combination treatment in the resistant cells gave additive rather than synergistic cytotoxicity. We concluded that IGF-1R is an independent druggable target in ALK-positive lung cancer and support the trial of combination treatment.

show abstract

Section: Discussionmentioning

confidence: 99%

ALK and IGF-1R as independent targets in crizotinib resistant lung cancer

Wilson

Nimick

Nehoff

et al. 2017

Sci Rep

View full text Add to dashboard Cite

show abstract

“…It has been shown to be effective in inhibiting various types of cancers including those of the gastrointestinal tract, nasopharynx, liver, lung, ovary, soft tissues, and hematopoietic system including NPM-ALK + T cell lymphoma [21, 34–46]. Recently, however, higher doses of PPP have been shown to induce bone marrow toxicity in some patients [30]. In this paper, we tested the hypothesis that dual suppression of ALK and IGF-IR could represent a superior strategy that significantly improves the effects of the isolated inhibition of each enzyme alone.…”

Section: Introductionmentioning

confidence: 99%

Dual inhibition of IGF-IR and ALK as an effective strategy to eradicate NPM-ALK+ T-cell lymphoma

George

Shi

et al. 2019

J Hematol Oncol

Self Cite

View full text Add to dashboard Cite

Background Nucleophosmin-anaplastic lymphoma kinase-expressing (NPM-ALK + ) T cell lymphoma is an aggressive neoplasm. NPM-ALK, an oncogenic tyrosine kinase, plays a critical role in this lymphoma. Recently, selective ALK inhibitors have emerged as a first-line therapy for this neoplasm. Unfortunately, ALK inhibitors were hindered by emergence of resistance and relapse. We have previously demonstrated that type I insulin-like growth factor receptor (IGF-IR) is commonly expressed and activated in this lymphoma. In addition, IGF-IR and NPM-ALK are physically associated and reciprocally enhance their phosphorylation/activation. Herein, we tested the hypothesis that combined inhibition of IGF-IR and NPM-ALK could significantly improve the effects of inhibiting each kinase alone. Methods We used clinically utilized inhibitors of IGF-IR (picropodophyllin; PPP) and ALK (ASP3026) to assess the in vitro cellular effects of combined treatment versus treatment using a single agent. Moreover, we used a systemic NPM-ALK + T cell lymphoma mouse model to analyze the in vivo effects of PPP and ASP3026 alone or in combination. Results Our data show that combined treatment with PPP and ASP3026 decreased the viability, proliferation, and anchorage-independent colony formation, and increased apoptosis of NPM-ALK + T cell lymphoma cells in vitro. The in vitro effects of combined treatment were synergistic and significantly more pronounced than the effects of PPP or ASP3026 alone. Biochemically, simultaneous antagonism of IGF-IR and ALK induced more pronounced decrease in pIGF-IR Y1135/1136 , pNPM-ALK Y646 , and pSTAT3 Y705 levels than antagonizing IGF-IR or ALK alone. Moreover, combined targeting of IGF-IR and NPM-ALK decreased significantly systemic lymphoma tumor growth and improved mice survival in vivo. Consistent with the in vitro results, the in vivo effects of the combined therapy were more pronounced than the effects of targeting IGF-IR or ALK alone. Conclusions Combined targeting of IGF-IR and ALK is more effective than targeting IGF-IR or ALK alone in NPM-ALK + T cell lymphoma. This strategy might also limit emergence of resistance to high doses of ALK inhibitors. Therefore, it could represent a successful therapeutic approach to eradicate this aggressive lymphoma. Importantly, combined inhibition is feasible because of the clinical availability of IGF-IR and ALK inhibitors. Our findings are applicable to other types of cancer where IGF-IR and ALK are simultaneously expressed. Electronic supplementary material The online version of this article (10.1186/s13045-019-0768-8) contains supplementary material, which is available to authorized users.

show abstract

“…Yet, small molecule IGF1R inhibitors-as well as inhibitors of other components of the IGF1R pathway-may still hold clinical potential when used in combination therapies. For example, combination of AXL1717 (picropodophyllin), an IGF1R pathway inhibitor, with gemcitabine HCl and carboplatin yielded an acceptable toxicity profile in previously untreated, locally advanced, or metastatic NSCLC (Holgersson et al, 2015). Similarly, BMS-754807 is a reversible small molecule inhibitor of IGF1R and insulin receptor (IR) (Carboni et al, 2009) that has demonstrated effectiveness in vitro in combination with anti-cancer therapies for the treatments of breast, pancreatic, colon, lung, and gastric cancers (Carboni et al, 2009).…”

Section: Pharmacological Autophagy Modulation As An Approach To Cancementioning

confidence: 99%

Dietary Energy Modulation and Autophagy: Exploiting Metabolic Vulnerabilities to Starve Cancer

Cozzo

Coleman

Pearce

et al. 2020

Front. Cell Dev. Biol.

View full text Add to dashboard Cite

Cancer cells experience unique and dynamic shifts in their metabolic function in order to survive, proliferate, and evade growth inhibition in the resource-scarce tumor microenvironment. Therefore, identification of pharmacological agents with potential to reprogram cancer cell metabolism may improve clinical outcomes in cancer therapy. Cancer cells also often exhibit an increased dependence on the process known as autophagy, both for baseline survival and as a response to stressors such as chemotherapy or a decline in nutrient availability. There is evidence to suggest that this increased dependence on autophagy in cancer cells may be exploitable clinically by combining autophagy modulators with existing chemotherapies. In light of the increased metabolic rate in cancer cells, interest is growing in approaches aimed at "starving" cancer through dietary and pharmacologic interventions that reduce availability of nutrients and pro-growth hormonal signals known to promote cancer progression. Several dietary approaches, including chronic calorie restriction and multiple forms of fasting, have been investigated for their potential anti-cancer benefits, yielding promising results in animal models. Induction of autophagy in response to dietary energy restriction may underlie some of the observed benefit. However, while interventions based on dietary energy restriction have demonstrated safety in clinical trials, uncertainty remains regarding translation to humans as well as feasibility of achieving compliance due to the potential discomfort and weight loss that accompanies dietary restriction. Further induction of autophagy through dietary or pharmacologic metabolic reprogramming interventions may enhance the efficacy of autophagy inhibition in the context of adjuvant or neo-adjuvant chemotherapy. Nonetheless, it remains unclear whether therapeutic agents aimed at autophagy induction, autophagy inhibition, or both are a viable therapeutic strategy for improving cancer outcomes. This review discusses the literature available for the therapeutic potential of these approaches.

show abstract

A phase I pilot study of the insulin-like growth factor 1 receptor pathway modulator AXL1717 in combination with gemcitabine HCl and carboplatin in previously untreated, locally advanced, or metastatic non-small cell lung cancer

Cited by 13 publications

References 14 publications

ALK and IGF-1R as independent targets in crizotinib resistant lung cancer

ALK and IGF-1R as independent targets in crizotinib resistant lung cancer

Dual inhibition of IGF-IR and ALK as an effective strategy to eradicate NPM-ALK+ T-cell lymphoma

Dietary Energy Modulation and Autophagy: Exploiting Metabolic Vulnerabilities to Starve Cancer

Contact Info

Product

Resources

About