9013 POSTER DISCUSSION Phase I Dose-escalation Study of AXL1717: a Novel Targeted Oral Insulin-like Growth Factor-1 Receptor (IGF-1R) Inhibitor and Its Implications for Patients With Non-small Cell Lung Carcinoma

Ekman, Simon; Harmenberg, Johan; Ståhl, Birgitta; Hedlund, Åsa; Bergström, Stefan; Frödin, Jan Erik; Bergqvist, Michael

doi:10.1016/s0959-8049(11)72325-5

Cited by 3 publications

(5 citation statements)

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“…There is as yet little consistent evidence regarding candidate tissue biomarkers for response to IGF-1R antibodies and TKIs, and it is not clear at this stage whether the same parameters will influence sensitivity to IGF ligand antibodies, which are still at a relatively early stage of development. However, enough trials have highlighted the association between response to IGF-1R inhibition and circulating IGFs, IGFBPs, and indicators of glycemic control [63,80–82,86,87,155] to support inclusion of these parameters in future trials of agents that remain under active investigation, for example [21,22,51,165]. Even amongst the failed trials, there are subsets of patients who have obtained durable benefit from IGF-1R inhibition.…”

Section: Resultsmentioning

confidence: 99%

“…There is as yet little evidence regarding the efficacy of ligand antibodies and non-ATP binding IGF-1R inhibitors, although of note, initial reports of the latter suggest single agent activity in non-small cell lung cancer (NSCLC) [28,51]. Otherwise, it is clear that in common cancers there is insufficient clinical support for continued evaluation of IGF-1R antibodies and TKIs as monotherapy in unselected patients.…”

Section: Clinical Trials: Reality Checkmentioning

confidence: 99%

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Can we unlock the potential of IGF-1R inhibition in cancer therapy?

King

Aleksic

Haluska

et al. 2014

Cancer Treatment Reviews

120

132

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IGF-1R inhibitors arrived in the clinic accompanied by optimism based on preclinical activity of IGF-1R targeting, and recognition that low IGF bioactivity protects from cancer. This was tempered by concerns about toxicity to normal tissue IGF-1R and cross-reactivity with insulin receptor (InsR). In fact, toxicity is not a show-stopper; the key issue is efficacy. While IGF-1R inhibition induces responses as monotherapy in sarcomas and with chemotherapy or targeted agents in common cancers, negative Phase 2/3 trials in unselected patients prompted the cessation of several Pharma programs. Here, we review completed and on-going trials of IGF-1R antibodies, kinase inhibitors and ligand antibodies. We assess candidate bio-markers for patient selection, highlighting the potential predictive value of circulating IGFs/IGFBPs, the need for standardized assays for IGF-1R, and preclinical evidence that variant InsRs mediate resistance to IGF-1R antibodies. We review hypothesis-led and unbiased approaches to evaluate IGF-1R inhibitors with other agents, and stress the need to consider sequencing with chemotherapy. The last few years were a tough time for IGF-1R therapeutics, but also brought progress in understanding IGF biology. Even failed studies include patients who derived benefit; they should be investigated to identify features distinguishing the tumors and host environment of responders from non-responders. We emphasize the importance of incorporating biospecimen collection into trial design, and wording patient consents to allow post hoc analysis of trial material as new data become available. Such information represents the key to unlocking the potential of this approach, to inform the next generation of trials of IGF signalling inhibitors.

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Section: Resultsmentioning

confidence: 99%

Section: Clinical Trials: Reality Checkmentioning

confidence: 99%

Can we unlock the potential of IGF-1R inhibition in cancer therapy?

King

Aleksic

Haluska

et al. 2014

Cancer Treatment Reviews

120

132

View full text Add to dashboard Cite

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“…diarrhea, melena and paralytic ileus, are probably explained by the high proliferative activity in the intestinal mucosa. No drug-related, clinically important gastrointestinal or neurological events have been reported after oral administration of PPP in the clinic [11, 12]. These early clinical data indicate that PPP does not show the typical side effects of general microtubule inhibitors thus suggesting that PPP might affect microtubule dynamics in a different manner than currently available drugs.…”

Section: Discussionmentioning

confidence: 99%

“…PPP is presently undergoing clinical development in non-small cell lung cancer (NSCLC) and in glioblastoma. Tumor response was indicated in NSCLC patients included in the first clinical study, despite PPP given as third or fourth line treatment [11, 12]. …”

Section: Introductionmentioning

confidence: 99%

Picropodophyllin causes mitotic arrest and catastrophe by depolymerizing microtubules via Insulin-like growth factor-1 receptor-independent mechanism

et al. 2014

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Picropodophyllin (PPP) is an anticancer drug undergoing clinical development in NSCLC. PPP has been shown to suppress IGF-1R signaling and to induce a G2/M cell cycle phase arrest but the exact mechanisms remain to be elucidated.The present study identified an IGF-1-independent mechanism of PPP leading to pro-metaphase arrest. The mitotic block was induced in human cancer cell lines and in an A549 xenograft mouse but did not occur in normal hepatocytes/mouse tissues.Cell cycle arrest by PPP occurred in vitro and in vivo accompanied by prominent CDK1 activation, and was IGF-1R-independent since it occurred also in IGF-1R-depleted and null cells. The tumor cells were not arrested in G2/M but in mitosis. Centrosome separation was prevented during mitotic entry, resulting in a monopolar mitotic spindle with subsequent prometaphase-arrest, independent of Plk1/Aurora A or Eg5, and leading to cell features of mitotic catastrophe. PPP also increased soluble tubulin and decreased spindle-associated tubulin within minutes, indicating that it interfered with microtubule dynamics.These results provide a novel IGF-1R-independent mechanism of antitumor effects of PPP.

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“…Furthermore, PPP specifically blocks the phosphorylation of a tyrosine residue, Tyr1136, within the activation loop of the IGF-IR (9). PPP is currently being investigated in clinical trials (under the name AXL1717) and the results that have been presented to date suggest that it has at least some useful clinical activity and exhibits only modest toxicity (10)(11)(12). As such, it is quite different to previously tested IGF-IR antagonists in both respects.…”

Section: Introductionmentioning

confidence: 99%

Alternative Cytotoxic Effects of the Postulated IGF-IR Inhibitor Picropodophyllin In Vitro

Sooman

Wickström

et al. 2013

Molecular Cancer Therapeutics

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The insulin-like growth factor-1 (IGF-I) and its receptors play an important role in transformation and progression of several malignancies. Inhibitors of this pathway have been developed and evaluated but generally performed poorly in clinical trials, and several drug candidates have been abandoned. The cyclolignan picropodophyllin (PPP) has been described as a potent and selective IGF-IR inhibitor and is currently undergoing clinical trials. We investigated PPP's activity in panels of human cancer cell lines (e.g., esophageal squamous carcinoma cell lines) but found no effects on the phosphorylation or expression of IGF-IR. Nor was the cytotoxic activity of PPP related to the presence or spontaneous phosphorylation of IGF-IR. However, its activity correlated with that of known tubulin inhibitors, and it destabilized microtubule assembly at cytotoxic concentrations also achievable in patients. PPP is a stereoisomer of podophyllotoxin (PPT), a potent tubulin inhibitor, and an equilibrium between the two has previously been described. PPP could thus potentially act as a reservoir for the continuous generation of low doses of PPT. Interestingly, PPP also inhibited downstream signaling from tyrosine kinase receptors, including the serine/threonine kinase Akt. This effect is associated with microtubule-related downregulation of the EGF receptor, rather than the IGF-IR. These results suggest that the cytotoxicity and pAkt inhibition observed following treatment with the cyclolignan PPP in vitro result from microtubule inhibition (directly or indirectly by spontaneous PPT formation), rather than any effect on IGF-IR. It is also suggested that PPT should be used as a reference compound in all future studies on PPP. Mol Cancer Ther; 12(8); 1526-36. Ó2013 AACR.

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9013 POSTER DISCUSSION Phase I Dose-escalation Study of AXL1717: a Novel Targeted Oral Insulin-like Growth Factor-1 Receptor (IGF-1R) Inhibitor and Its Implications for Patients With Non-small Cell Lung Carcinoma

Cited by 3 publications

References 0 publications

Can we unlock the potential of IGF-1R inhibition in cancer therapy?

Can we unlock the potential of IGF-1R inhibition in cancer therapy?

Picropodophyllin causes mitotic arrest and catastrophe by depolymerizing microtubules via Insulin-like growth factor-1 receptor-independent mechanism

Alternative Cytotoxic Effects of the Postulated IGF-IR Inhibitor Picropodophyllin In Vitro

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