Inhibition of mTOR signaling and clinical activity of metformin in oral premalignant lesions

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Abstract

BACKGROUND

The aberrant activation of the PI3K/mTOR signaling circuitry is one of the most frequently dysregulated signaling events in head and neck squamous cell carcinoma (HNSCC). Here, we conducted a single-arm, open-label phase IIa clinical trial in individuals with oral premalignant lesions (OPLs) to explore the potential of metformin to target PI3K/mTOR signaling for HNSCC prevention.

METHODS

Individuals with OPLs, but who were otherwise healthy and without diabetes, underwent pretreatment and posttreatment clinical exam and biopsy. Participants received metformin for 12 weeks (week 1, 500 mg; week 2, 1000 mg; weeks 3–12, 2000 mg daily). Pretreatment and posttreatment biopsies, saliva, and blood were obtained for biomarker analysis, including IHC assessment of mTOR signaling and exome sequencing.

RESULTS

Twenty-three participants were evaluable for response. The clinical response rate (defined as a ≥50% reduction in lesion size) was 17%. Although lower than the proposed threshold for favorable clinical response, the histological response rate (improvement in histological grade) was 60%, including 17% complete responses and 43% partial responses. Logistic regression analysis revealed that when compared with never smokers, current and former smokers had statistically significantly increased histological responses ( P = 0.016). Remarkably, a significant correlation existed between decreased mTOR activity (pS6 IHC staining) in the basal epithelial layers of OPLs and the histological ( P = 0.04) and clinical ( P = 0.01) responses.

CONCLUSION

To our knowledge this is the first phase II trial of metformin in individuals with OPLs, providing evidence that metformin administration results in encouraging histological responses and mTOR pathway modulation, thus supporting its further investigation as a chemopreventive agent.

TRIAL REGISTRATION

NCT02581137

FUNDING

NIH contract HHSN261201200031I, grants R01DE026644 and R01DE026870

Abstract

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Most cited references 48

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Cancer statistics, 2020

Rebecca Siegel, Kimberly D Miller, Ahmedin Jemal (2020)

Each year, the American Cancer Society estimates the numbers of new cancer cases and deaths that will occur in the United States and compiles the most recent data on population-based cancer occurrence. Incidence data (through 2016) were collected by the Surveillance, Epidemiology, and End Results Program; the National Program of Cancer Registries; and the North American Association of Central Cancer Registries. Mortality data (through 2017) were collected by the National Center for Health Statistics. In 2020, 1,806,590 new cancer cases and 606,520 cancer deaths are projected to occur in the United States. The cancer death rate rose until 1991, then fell continuously through 2017, resulting in an overall decline of 29% that translates into an estimated 2.9 million fewer cancer deaths than would have occurred if peak rates had persisted. This progress is driven by long-term declines in death rates for the 4 leading cancers (lung, colorectal, breast, prostate); however, over the past decade (2008-2017), reductions slowed for female breast and colorectal cancers, and halted for prostate cancer. In contrast, declines accelerated for lung cancer, from 3% annually during 2008 through 2013 to 5% during 2013 through 2017 in men and from 2% to almost 4% in women, spurring the largest ever single-year drop in overall cancer mortality of 2.2% from 2016 to 2017. Yet lung cancer still caused more deaths in 2017 than breast, prostate, colorectal, and brain cancers combined. Recent mortality declines were also dramatic for melanoma of the skin in the wake of US Food and Drug Administration approval of new therapies for metastatic disease, escalating to 7% annually during 2013 through 2017 from 1% during 2006 through 2010 in men and women aged 50 to 64 years and from 2% to 3% in those aged 20 to 49 years; annual declines of 5% to 6% in individuals aged 65 years and older are particularly striking because rates in this age group were increasing prior to 2013. It is also notable that long-term rapid increases in liver cancer mortality have attenuated in women and stabilized in men. In summary, slowing momentum for some cancers amenable to early detection is juxtaposed with notable gains for other common cancers.

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Comprehensive genomic characterization of head and neck squamous cell carcinomas

Akinyemi Ojesina, Nikolaus Schultz (2015)

The Cancer Genome Atlas profiled 279 head and neck squamous cell carcinomas (HNSCCs) to provide a comprehensive landscape of somatic genomic alterations. We find that human papillomavirus-associated (HPV) tumors are dominated by helicase domain mutations of the oncogene PIK3CA, novel alterations involving loss of TRAF3, and amplification of the cell cycle gene E2F1. Smoking-related HNSCCs demonstrate near universal loss of TP53 mutations and CDKN2A with frequent copy number alterations including a novel amplification of 11q22. A subgroup of oral cavity tumors with favorable clinical outcomes displayed infrequent CNAs in conjunction with activating mutations of HRAS or PIK3CA, coupled with inactivating mutations of CASP8, NOTCH1 and wild-type TP53. Other distinct subgroups harbored novel loss of function alterations of the chromatin modifier NSD1, Wnt pathway genes AJUBA and FAT1, and activation of oxidative stress factor NFE2L2, mainly in laryngeal tumors. Therapeutic candidate alterations were identified in the majority of HNSCC's.

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The insulin and insulin-like growth factor receptor family in neoplasia: an update.

Michael Pollak (2012)

Although several early phase clinical trials raised enthusiasm for the use of insulin-like growth factor I receptor (IGF1R)-specific antibodies for cancer treatment, initial Phase III results in unselected patients have been disappointing. Further clinical studies may benefit from the use of predictive biomarkers to identify probable responders, the use of rational combination therapies and the consideration of alternative targeting strategies, such as ligand-specific antibodies and receptor-specific tyrosine kinase inhibitors. Targeting insulin and IGF signalling also needs to be considered in the broader context of the pathophysiology that relates obesity and diabetes to neoplasia, and the effects of anti-diabetic drugs, including metformin, on cancer risk and prognosis. The insulin and IGFI receptor family is also relevant to the development of PI3K-AKT pathway inhibitors.

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Author and article information

Contributors

J. Silvio Gutkind:

ORCID: http://orcid.org/0000-0002-5150-4482

Xingyu Wu

Zhiyong Wang:

ORCID: http://orcid.org/0000-0002-3574-6078

Daniela Nachmanson

Olivier Harismendy:

ORCID: http://orcid.org/0000-0002-8098-9888

Ludmil B. Alexandrov:

ORCID: http://orcid.org/0000-0003-3596-4515

Beverly R. Wuertz:

ORCID: http://orcid.org/0000-0002-2583-9043

Frank G. Ondrey

Leigha D. Rock:

ORCID: http://orcid.org/0000-0002-7258-3837

Valerie D. Butler

Lisa Bengtson

Chiu-Hsieh Hsu

Julie E. Bauman

Stephen M. Hewitt:

ORCID: http://orcid.org/0000-0001-8283-1788

Ezra E.W. Cohen

Scott M. Lippman

Eva Szabo

Journal

Journal ID (nlm-ta): JCI Insight

Journal ID (iso-abbrev): JCI Insight

Journal ID (publisher-id): JCI Insight

Title: JCI Insight

Publisher: American Society for Clinical Investigation

ISSN (Electronic): 2379-3708

Publication date (Electronic, pub): 8 September 2021

Publication date (Electronic, collection): 8 September 2021

Publication date PMC-release: 8 September 2021

Volume: 6

Issue: 17

Electronic Location Identifier: e147096

Affiliations

[1 ]Moores Cancer Center, University of California, San Diego (UCSD), La Jolla, California, USA.

[2 ]Department of Pharmacology, UCSD School of Medicine, La Jolla, California, USA.

[3 ]Bioinformatics and Systems Biology Graduate Program, UCSD, La Jolla, California, USA.

[4 ]Division of Biomedical Informatics, Department of Medicine, UCSD School of Medicine, La Jolla, California, USA.

[5 ]Department of Otolaryngology, Head and Neck Surgery, University of Minnesota (UMN), Minneapolis, Minnesota, USA.

[6 ]Department of Oral Biological and Medical Sciences, Faculty of Dentistry, University of British Columbia, Vancouver, British Columbia, Canada.

[7 ]British Columbia Cancer Agency (BCCA), British Columbia Agency Research Center, Vancouver, British Columbia, Canada.

[8 ]University of Arizona Cancer Center, Tucson, Arizona, USA.

[9 ]Division of Cancer Prevention and

[10 ]Center for Cancer Research, NCI, Bethesda, Maryland, USA.

Author notes

Address correspondence to: J. Silvio Gutkind, Moores Cancer Center, University of California, San Diego, 3855 Health Sciences Drive, Room 2344, La Jolla, California 92093, USA. Phone: 858.534.5980; Email: sgutkind@ 123456ucsd.edu . Or to: Eva Szabo, Division of Cancer Prevention, National Cancer Institute, 9609 Medical Center Drive, Room 5E102, MSC 9781, Bethesda, Maryland 20892, USA. Phone: 240.276.7011; Email: szaboe@ 123456mail.nih.gov .

Author information

J. Silvio Gutkind http://orcid.org/0000-0002-5150-4482

Zhiyong Wang http://orcid.org/0000-0002-3574-6078

Olivier Harismendy http://orcid.org/0000-0002-8098-9888

Ludmil B. Alexandrov http://orcid.org/0000-0003-3596-4515

Beverly R. Wuertz http://orcid.org/0000-0002-2583-9043

Leigha D. Rock http://orcid.org/0000-0002-7258-3837

Stephen M. Hewitt http://orcid.org/0000-0001-8283-1788

Article

Publisher ID: 147096

DOI: 10.1172/jci.insight.147096

PMC ID: 8492350

PubMed ID: 34255745

SO-VID: 199c4ff8-6eee-45c0-b4d2-092ddcb7c9be

License:

This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

History

Date received : 22 December 2020

Date accepted : 7 July 2021

Funding

Funded by: National Cancer Institute (NCI)

Award ID: HHSN261201200031I

Funded by: NIDCR

Award ID: R01DE026644

Funded by: NIDCR

Award ID: R01DE026870

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Inhibition of mTOR signaling and clinical activity of metformin in oral premalignant lesions

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Abstract

BACKGROUND

METHODS

RESULTS

CONCLUSION

TRIAL REGISTRATION

FUNDING

Abstract

Related collections

Drug Repurposing

Most cited references 48

Cancer statistics, 2020

Comprehensive genomic characterization of head and neck squamous cell carcinomas

The insulin and insulin-like growth factor receptor family in neoplasia: an update.

Author and article information

Contributors

Journal

Affiliations

Author notes

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Article

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Comments

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Cited by 12

Most referenced authors 928