A Phase I Dose-Escalation Study of Linsitinib (OSI-906), a Small-Molecule Dual Insulin-Like Growth Factor-1 Receptor/Insulin Receptor Kinase Inhibitor, in Combination with Irinotecan in Patients with Advanced Cancer

Davis, S. Lindsey; Eckhardt, S. Gail; Diamond, Jennifer R.; Messersmith, Wells A.; Dasari, Arvind; Weekes, Colin D.; Lieu, Christopher H.; Kane, Madeline; Tan, Aik Choon; Pitts, Todd M.; Leong, Stephen

doi:10.1634/theoncologist.2018-0315

Cited by 7 publications

(8 citation statements)

References 13 publications

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“…In this context, the failure of the clinical trials (and the many compounds which have not passed the preclinical stage) for all those drugs directed against the IGF1R (reviewed in Table 1A,B) did not come as a surprise, in contrast to the main supporters of its direct targeting [68]. Even the strategy of a double block of the IGF1R and the IR would have the same limits (and counter-effects) as shown by the clinical trials of linsitinib [99][100][101][102][103], a small molecule inhibiting both RTK receptors. This led to a recent approach conveyed in the development of xentuzumab and disigitumab (double anti-IGF1/IGF2 MAbs), targeting the known IGF ligands rather than their RTKs [104][105][106], currently in phase I testing.…”

Section: Learning From the Igf System Targeting In Cancer: Not All LImentioning

confidence: 99%

The IGF-II–Insulin Receptor Isoform-A Autocrine Signal in Cancer: Actionable Perspectives

Scalia

Giordano

2020

Cancers

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Insulin receptor overexpression is a common event in human cancer. Its overexpression is associated with a relative increase in the expression of its isoform A (IRA), a shorter variant lacking 11 aa in the extracellular domain, conferring high affinity for the binding of IGF-II along with added intracellular signaling specificity for this ligand. Since IGF-II is secreted by the vast majority of malignant solid cancers, where it establishes autocrine stimuli, the co-expression of IGF-II and IRA in cancer provides specific advantages such as apoptosis escape, growth, and proliferation to those cancers bearing such a co-expression pattern. However, little is known about the exact role of this autocrine ligand–receptor system in sustaining cancer malignant features such as angiogenesis, invasion, and metastasis. The recent finding that the overexpression of angiogenic receptor kinase EphB4 along with VEGF-A is tightly dependent on the IGF-II/IRA autocrine system independently of IGFIR provided new perspectives for all malignant IGF2omas (those aggressive solid cancers secreting IGF-II). The present review provides an updated view of the IGF system in cancer, focusing on the biology of the autocrine IGF-II/IRA ligand–receptor axis and supporting its underscored role as a malignant-switch checkpoint target.

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Section: Learning From the Igf System Targeting In Cancer: Not All LImentioning

confidence: 99%

The IGF-II–Insulin Receptor Isoform-A Autocrine Signal in Cancer: Actionable Perspectives

Scalia

Giordano

2020

Cancers

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“…Secondly, our data underline existing clinical approaches for cancer screening in patients with disorders of GH-IGF1 axis overactivity 13 , and may suggest extension of such protocols beyond colorectal cancer. Thirdly, our findings may encourage renewed interest in use of anti-IGF1 therapies for cancer outcomes 41,42 .…”

Section: Discussionmentioning

confidence: 77%

Elucidating the genetic architecture underlying IGF1 levels and its impact on genomic instability and cancer risk

et al. 2021

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Background: Insulin-like growth factor-1 (IGF1) has been implicated in mitogenic and anti-apoptotic mechanisms that promote susceptibility to cancer development and growth. Previous epidemiological studies have described phenotypic associations between higher circulating levels of IGF1 in adults with higher risks for breast, prostate, ovarian, colorectal, melanoma and lung cancers. However, such evidence is prone to confounding and reverse causality. Furthermore, it is unclear whether IGF1 promotes only the survival and proliferation of cancerous cells, or also the malignant transformation of healthy cells. Methods: We perform a genome-wide association study in 428,525 white European ancestry individuals in the UK Biobank study (UKBB) and identify 831 independent genetic determinants of circulating IGF1 levels, double the number previously reported. Results: Collectively these signals explain ~7.5% of the variance in circulating IGF1 levels in EPIC-Norfolk, with individuals in the highest 10% of genetic risk exhibiting ~1 SD higher levels than those in the lowest 10%. Using a Mendelian randomization approach, we demonstrate that genetically higher circulating IGF1 levels are associated with greater likelihood of mosaic loss of chromosome Y in leukocytes in men in UKBB (OR per +1 SD = 1.038 (95% CI: 1.010-1.067), P=0.008) and 23andMe, Inc. (P=6.8×10-05), a biomarker of genomic instability involved in early tumorigenesis. Genetically higher IGF1 is also associated with higher risks for colorectal (OR = 1.126 (1.048-1.210), P=1.3×10-03) and breast cancer (OR= 1.075 (1.048-1.103), P=3.9×10-08), with similar effects on estrogen positive (ER+) (OR = 1.069 (1.037-1.102), P=2.3×10-05) and estrogen negative (ER-) (OR = 1.074 (1.025-1.125), P=3.9×10-08) subtypes. Conclusions: These findings give an insight into the genetic regulation of circulating IGF1 levels and support a causal role for IGF1 in early tumorigenesis and risks for breast and colorectal cancers.

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“…[55][56][57] Linsitinib increased the efficacy of immunochemotherapy in mice, suggesting that this type of clinical grade IGF1R inhibitor should be evaluated in patients for similar combination effects. Indeed, linsitinib has been administered to patients with cancer either alone [55][56][57] or in combination with other anticancer agents thought to mediate direct effects on cancer cells such as the MTORC1 inhibitor everolimus, 58 the EGFR inhibitor erlotinib 59 or the chemotherapeutics paclitaxel 60 and irinothecan, 61 with variable results. However, linsitinib has not been investigated for its potential immune effects and has not been combined with any kind of immunotherapy including PD-1 blockade.…”

Section: Discussionmentioning

confidence: 99%

IGF1 receptor inhibition amplifies the effects of cancer drugs by autophagy and immune-dependent mechanisms

Tian

et al. 2021

J Immunother Cancer

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BackgroundPharmacological autophagy enhancement constitutes a preclinically validated strategy for preventing or treating most major age-associated diseases. Driven by this consideration, we performed a high-content/high-throughput screen on 65 000 distinct compounds on a robotized fluorescence microscopy platform to identify novel autophagy inducers.ResultsHere, we report the discovery of picropodophyllin (PPP) as a potent inducer of autophagic flux that acts on-target, as an inhibitor of the tyrosine kinase activity of the insulin-like growth factor-1 receptor (IGF1R). Thus, PPP lost its autophagy-stimulatory activity in cells engineered to lack IGF1R or to express a constitutively active AKT serine/threonine kinase 1 (AKT1) mutant. When administered to cancer-bearing mice, PPP improved the therapeutic efficacy of chemoimmunotherapy with a combination of immunogenic cytotoxicants and programmed cell death 1 (PDCD1, better known as PD-1) blockade. These PPP effects were lost when tumors were rendered PPP-insensitive or autophagy-incompetent. In combination with chemotherapy, PPP enhanced the infiltration of tumors by cytotoxic T lymphocytes, while reducing regulatory T cells. In human triple-negative breast cancer patients, the activating phosphorylation of IGF1R correlated with inhibited autophagy, an unfavorable local immune profile, and poor prognosis.ConclusionAltogether, these results suggest that IGF1R may constitute a novel and druggable therapeutic target for the treatment of cancer in conjunction with chemoimmunotherapies.

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A Phase I Dose-Escalation Study of Linsitinib (OSI-906), a Small-Molecule Dual Insulin-Like Growth Factor-1 Receptor/Insulin Receptor Kinase Inhibitor, in Combination with Irinotecan in Patients with Advanced Cancer

Abstract: Although the combination was determined safe, the study was halted due to termination of linsitinib development, and biomarker testing was not performed.

Cited by 7 publications

References 13 publications

The IGF-II–Insulin Receptor Isoform-A Autocrine Signal in Cancer: Actionable Perspectives

The IGF-II–Insulin Receptor Isoform-A Autocrine Signal in Cancer: Actionable Perspectives

Elucidating the genetic architecture underlying IGF1 levels and its impact on genomic instability and cancer risk

IGF1 receptor inhibition amplifies the effects of cancer drugs by autophagy and immune-dependent mechanisms

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