Selective inhibition of SCLC growth by the A12 anti-IGF-1R monoclonal antibody correlates with inhibition of Akt

Yeh, Juddi; Litz, Julie; Hauck, Paula M.; Ludwig, Dale L.; Krystal, Geoffrey W.

doi:10.1016/j.lungcan.2007.09.023

Cited by 33 publications

(21 citation statements)

References 17 publications

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“…While PTEN loss amplifies signalling to AKT, it does not induce constitutive pathway activation; logic dictates that constitutively activating mutations in the PI3K-AKT or RAS-RAF-ERK pathways should render cells refractory to IGF axis blockade. Indeed, preclinical data suggest that resistance to IGF-1R inhibition is observed in the context of constitutive AKT activation and high levels of activated ERKs [108–111], and sensitivity of KRAS mutant NSCLC was restored by MEK inhibition [112,113]. Consistent with this, IGF-1R antibody ganitumab was ineffective at sensitizing to FOLFIRI chemotherapy in patients with KRAS mutant colorectal cancer [114], although issues of chemotherapy scheduling may be a contributing factor (see below).…”

Section: Can We Identify Who Will Benefit?mentioning

confidence: 99%

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

King

Aleksic

Haluska

et al. 2014

Cancer Treatment Reviews

123

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: Can We Identify Who Will Benefit?mentioning

confidence: 99%

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

King

Aleksic

Haluska

et al. 2014

Cancer Treatment Reviews

123

132

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“…61 IMC-A12 causes growth inhibition and chemosensitization in SCLC cell lines when PI3K-AKT signaling is also inhibited. 62 Using NVP-ADW742 alone leads to potent antitumor activity, yet by combining AG1024 and AG1296, inhibitors of IGFR-1 and c-kit, respectively, there is synergy in proliferation, inhibition and apoptosis induction in SCLC. 63,64 Fibroblast growth factor receptor.…”

Section: Intracellular Molecular Chaperonesmentioning

confidence: 99%

The molecular pathogenesis of small cell lung cancer

D’Angelo¹,

Pietanza²

2010

Cancer Biology & Therapy

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Small cell lung cancer (SCLC) represents 13% of all lung cancer cases diagnosed in the United States. Although a chemotherapy and radiation-sensitive disease, SCLC recurs rapidly with only 5% of patients surviving five years. This dismal prognosis likely is secondary to few improvements in its treatment, without significant changes in its standard of care over the last three decades. SCLC has a unique biology with specific molecular and cellular changes, which are the subject of active investigation. Here, we summarize the alterations leading to the pathogenesis of SCLC: chromosomal changes; dysregulation of tumor suppressor genes, oncogenes, and signaling pathways; upregulation of receptor tyrosine kinases, growth factors and cellular markers; and the persistence of developmental pathways. Each of these represents potential targets for therapy and many biologic agents are being studied.

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“…IMC-A12 treatment induced significant antitumour activity also in Colo205 and BxPC-3 xenografts, affecting tumour growth and showing >70% and 80% of growth inhibition, in Colo205 and BxPC-3 xenografts, respectively [179]. IMC-A12 has also shown potent activity, as a single agent, against xenograft models of human non-small cell and small cell lung carcinoma, as well as in models of prostate, renal, thyroid and head and neck carcinoma, multiple myeloma and sarcoma [180-183]. Nowadays, a Phase 2 study (NCT00639509) in patients with primary, advanced, localized unresectable, recurrent HCC, has been completed.…”

Section: Introductionmentioning

confidence: 99%

The GH-IGF-SST system in hepatocellular carcinoma: biological and molecular pathogenetic mechanisms and therapeutic targets

Pivonello

Martino

Negri

et al. 2014

Infect Agents Cancer

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Hepatocellular carcinoma (HCC) is the sixth most common malignancy worldwide. Different signalling pathways have been identified to be implicated in the pathogenesis of HCC; among these, GH, IGF and somatostatin (SST) pathways have emerged as some of the major pathways implicated in the development of HCC. Physiologically, GH-IGF-SST system plays a crucial role in liver growth and development since GH induces IGF1 and IGF2 secretion and the expression of their receptors, involved in hepatocytes cell proliferation, differentiation and metabolism. On the other hand, somatostatin receptors (SSTRs) are exclusively present on the biliary tract. Importantly, the GH-IGF-SST system components have been indicated as regulators of hepatocarcinogenesis. Reduction of GH binding affinity to GH receptor, decreased serum IGF1 and increased serum IGF2 production, overexpression of IGF1 receptor, loss of function of IGF2 receptor and appearance of SSTRs are frequently observed in human HCC. In particular, recently, many studies have evaluated the correlation between increased levels of IGF1 receptors and liver diseases and the oncogenic role of IGF2 and its involvement in angiogenesis, migration and, consequently, in tumour progression. SST directly or indirectly influences tumour growth and development through the inhibition of cell proliferation and secretion and induction of apoptosis, even though SST role in hepatocarcinogenesis is still opened to argument.This review addresses the present evidences suggesting a role of the GH-IGF-SST system in the development and progression of HCC, and describes the therapeutic perspectives, based on the targeting of GH-IGF-SST system, which have been hypothesised and experimented in HCC.

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Selective inhibition of SCLC growth by the A12 anti-IGF-1R monoclonal antibody correlates with inhibition of Akt

Cited by 33 publications

References 17 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?

The molecular pathogenesis of small cell lung cancer

The GH-IGF-SST system in hepatocellular carcinoma: biological and molecular pathogenetic mechanisms and therapeutic targets

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