Integrative Radiogenomic Profiling of Squamous Cell Lung Cancer

Abazeed, Mohamed E.; Adams, Drew J.; Hurov, Kristen E.; Tamayo, Pablo; Creighton, Chad J.; Sonkin, Dmitriy; Giacomelli, Andrew O.; Schreiber, Stuart L.; Hammerman, Peter S.; Meyerson, Matthew

doi:10.1016/j.ijrobp.2013.06.356

Cited by 14 publications

(18 citation statements)

References 30 publications

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“…Oxaliplatin is a first-line chemotherapeutic agent for colorectal cancer and also is used to treat pancreatic, gastric, and testicular cancers (27,28). It is an organoplatinum complex that is thought to produce cytotoxicity via the formation of DNA adducts that interfere with DNA replication and transcription, leading to the induction of apoptosis.…”

Section: Discussionmentioning

confidence: 99%

“…Wild-type mice were CBA/CaJ (The Jackson Laboratory). Germline α9 KO mice (28), originally on a 129Sv/Ev and CBA/CaJ background, were crossed using an accelerated backcrossing program (The Jackson Laboratory) until 99.5% identity with wild-type CBA/CaJ mice was achieved. Mice were then further backcrossed with wild-type CBA/CAJ mice for an additional three generations.…”

Section: Methodsmentioning

confidence: 99%

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Inhibition of α9α10 nicotinic acetylcholine receptors prevents chemotherapy-induced neuropathic pain

Romero

Christensen

Mannelli

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

142

204

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Opioids are first-line drugs for moderate to severe acute pain and cancer pain. However, these medications are associated with severe side effects, and whether they are efficacious in treatment of chronic nonmalignant pain remains controversial. Medications that act through alternative molecular mechanisms are critically needed. Antagonists of α9α10 nicotinic acetylcholine receptors (nAChRs) have been proposed as an important nonopioid mechanism based on studies demonstrating prevention of neuropathology after trauma-induced nerve injury. However, the key α9α10 ligands characterized to date are at least two orders of magnitude less potent on human vs. rodent nAChRs, limiting their translational application. Furthermore, an alternative proposal that these ligands achieve their beneficial effects by acting as agonists of GABA B receptors has caused confusion over whether blockade of α9α10 nAChRs is the fundamental underlying mechanism. To address these issues definitively, we developed RgIA4, a peptide that exhibits high potency for both human and rodent α9α10 nAChRs, and was at least 1,000-fold more selective for α9α10 nAChRs vs. all other molecular targets tested, including opioid and GABA B receptors. A daily s.c. dose of RgIA4 prevented chemotherapy-induced neuropathic pain in rats. In wild-type mice, oxaliplatin treatment produced cold allodynia that could be prevented by RgIA4. Additionally, in α9 KO mice, chemotherapy-induced development of cold allodynia was attenuated and the milder, temporary cold allodynia was not relieved by RgIA4. These findings establish blockade of α9-containing nAChRs as the basis for the efficacy of RgIA4, and that α9-containing nAChRs are a critical target for prevention of chronic cancer chemotherapyinduced neuropathic pain.pain | chemotherapy | alpha9 | nicotinic

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Inhibition of α9α10 nicotinic acetylcholine receptors prevents chemotherapy-induced neuropathic pain

Romero

Christensen

Mannelli

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

142

204

View full text Add to dashboard Cite

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“…In preclinical studies it has been shown to be active in suppressing proliferation and inducing apoptosis of cancer cell lines and in inhibiting the growth of human tumor xenografts in mice at tolerated doses (Maira et al, 2012;Koul et al, 2012). Abazeed et al reported that BKM120 decreased NRF2 protein levels and sensitized NFE2L2 or KEAP1-mutant squamous cell lung cancer cells to radiation and the resulting analysis of identified pathways implicated in cell survival, genotoxic stress, detoxification, and innate and adaptive immunity as key correlates of radiation sensitivity (Abazeed et al, 2013). Our data showed that BKM120 can sensitize CaP-RR cells developed in our lab (Chang et al, 2014b).…”

Section: Pi3k Inhibitorsmentioning

confidence: 99%

Targeting PI3K/Akt/mTOR signaling pathway in the treatment of prostate cancer radioresistance

Chang

Graham

et al. 2015

Critical Reviews in Oncology/Hematology

158

117

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“…PIK3CA overexpression (not mutation) has been associated with shorter OS in other cancers (18). Preclinical studies have demonstrated that patient-derived PIK3CA mutant HNSCC tumorgrafts are sensitive to PI3K/mTOR inhibitors (8), and PI3K pathway inhibition may sensitize cancer cells to radiation (19). Clinical trials of a PI3K inhibitor in combination with chemoradiation (NCT02113878) or chemotherapy alone (NCT01816984) are underway.…”

Section: % 3%mentioning

confidence: 99%

Incorporation of Next-Generation Sequencing into Routine Clinical Care to Direct Treatment of Head and Neck Squamous Cell Carcinoma

Chau

et al. 2016

Clinical Cancer Research

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Purpose: The clinical impact of next-generation sequencing (NGS) in patients with head and neck squamous cell carcinoma (HNSCC) has not been described. We aimed to evaluate the clinical impact of NGS in the routine care of patients with HNSCC and to correlate genomic alterations with clinical outcomes.Experimental Design: Single-center study examining targeted NGS platform used to sequence tumor DNA obtained from 213 HNSCC patients evaluated in outpatient head and neck oncology clinic between August 2011 and December 2014. We correlated tumor genomic profiling results with clinical outcomes.Results: PI3K/RTK pathway activation occurred frequently [activating PIK3CA mutation or amplification (13%), PTEN inactivation (3%), RAS activation (6%), EGFR or ERBB2 activation (9%)]. Alterations in pathways affecting cell-cycle regulation [CCND1 amplification (9%), CDKN2A inactivation (17%), BRCA2 inactivation (2%)] and squamous differentiation [NOTCH1 inactivation (8%) andEP300 inactivation (6%)] were identified. PIK3CA amplification (n ¼ 43), not PIK3CA mutation, was associated with significantly poorer progression-free survival (P ¼ 0.0006). Oncogenic RAS mutations (n ¼ 13) were associated with significantly poorer progression-free survival (P ¼ 0.0001) and lower overall survival (P ¼ 0.003). Eight patients with advanced, treatment-refractory HNSCC enrolled on clinical trials matched to tumor profiling results, and 50% achieved a partial response.Conclusions: Incorporation of NGS clinical assays into the routine care of patients with HNSCC is feasible and may readily facilitate enrollment into clinical trials of targeted therapy with a higher likelihood of success. Data can be utilized for discovery of genomic biomarkers of outcome. PIK3CA amplification and RAS mutations were frequently identified and associated with poorer prognosis in this cohort.

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Integrative Radiogenomic Profiling of Squamous Cell Lung Cancer

Cited by 14 publications

References 30 publications

Inhibition of α9α10 nicotinic acetylcholine receptors prevents chemotherapy-induced neuropathic pain

Inhibition of α9α10 nicotinic acetylcholine receptors prevents chemotherapy-induced neuropathic pain

Targeting PI3K/Akt/mTOR signaling pathway in the treatment of prostate cancer radioresistance

Incorporation of Next-Generation Sequencing into Routine Clinical Care to Direct Treatment of Head and Neck Squamous Cell Carcinoma

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