Heterogeneous Responses and Isoform Compensation Dim Therapeutic Window of Hsp90 ATP-Binding Inhibitors in Cancer

The rare capacity for heat shock protein-90 (Hsp90) chaperones to support almost the entire cellular signaling networks was viewed as a potential breakthrough point to combat tumor resistance to single oncogene-based therapeutics. Over two decades, several generations of Hsp90 ATP-binding inhibitors have entered numerous cancer clinical trials, but few have advanced to FDA approval for treatment of human cancers. Herein, we report that Hsp90 expression dramatically vary especially among different types of non-cancer cells and organs. The highly variable levels of Hsp90 from as low as 1.7% to as high as 9% of their total cellular proteins were responsible for either an extreme sensitivity or an extreme resistance to a classical Hsp90 ATP-binding inhibitor. Among randomly selected cancer cell lines, the same client proteins for regulation of cell growth exhibited unexpectedly heterogenous reactions in response to Hsp90 ATP-binding inhibitor, inconsistent with the current understanding. Finally, a minimum amount (<10%) of Hsp90β was still required for client protein stability and cell survival even in the presence of full Hsp90α. These new findings of Hsp90 expression in host and isoform compensation in tumor cells could complicate biomarker selection, toxicity readout and clinical efficacy of Hsp90-ATP-binding inhibitors in cancer clinical trials.

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Enrollment disparities in cancer clinical trials leading to FDA approvals between 2008 and 2020.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.e18501 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. e18501-e18501

Author(s):

Ryan Huu-Tuan Nguyen ◽

Yomaira Silva ◽

Vijayakrishna K. Gadi

Keyword(s):

Prostate Cancer ◽

United States ◽

Clinical Trials ◽

Drug Approval ◽

The United States ◽

Cancer Clinical Trials ◽

Cancer Prevalence ◽

Fda Approval ◽

The Us ◽

Enrollment Data

e18501 Background: Cancer clinical trials based in the United States (US) have lacked adequate representation of racial and ethnic minorities, the elderly, and women. Pivotal clinical trials leading to United States Food and Drug Administration (FDA) approval are often multi-national trials and may also lack generalizability to underrepresented populations in the United States. We determined the racial, ethnic, age, and sex enrollment in pivotal trials relative to the US cancer population. Methods: We reviewed the FDA’s Drug Approvals and Databases for novel and new use drug approvals for breast, colorectal, lung, and prostate cancer indications from 2008 through 2020. Drugs@FDA was searched for drug approval summaries and FDA labels to identify clinical trials used to justify clinical efficacy that led to FDA approval. For eligible trials, enrollment data were obtained from FDA approval summaries, FDA labels, ClinicalTrials.gov, and corresponding journal manuscripts. Enrollment Fraction (EF) was calculated as enrollment in identified clinical trials divided by 2017 SEER cancer prevalence. All data sources were publicly available. Results: From 2008 through 2020, 60 drugs received novel or new use drug approval for breast, colorectal, lung, or prostate cancer indications based on 66 clinical trials with a total enrollment of 36,830. North America accounted for 9,259 (31%) enrollees of the 73% of trials reporting location of enrollment. Racial demographics were reported in 78% of manuscripts, 66% of ClinicalTrials.gov pages, and 98% of FDA labels or approval summaries. Compared with a 0.4% enrollment fraction among White patients, lower enrollment fractions were noted in Hispanic (0.2%, odds ratio [OR] vs White, 0.46; 95% confidence interval [CI], 0.43 to 0.49, P< 0.001) and Black (0.1%, OR 0.29; 95% CI 0.28 to 0.31, P< 0.001) patients. Elderly patients (age ≥ 65 years) were less likely than younger patients to be enrollees (EF 0.3% vs 0.9%, OR 0.27; 95% CI 0.26 to 0.27, P< 0.001) despite accounting for 61.3% of cancer prevalence. For colorectal and lung cancer trials, females were less likely than males (EF 0.7% vs 1.1%, OR 0.66; 95% CI 0.63 to 0.68, P< 0.001) to be enrolled. Conclusions: Black, Hispanic, elderly, and female patients were less likely to enroll in cancer clinical trials leading to FDA approvals from 2008 to 2020. Race and geographic enrollment data were inconsistently reported in journal manuscripts and ClinicalTrials.gov. The lack of appropriate representation of specific patient populations in these key clinical trials limits their generalizability. Future efforts must be made to ensure equitable access, representation, and reporting of enrollees that adequately represent the US population of patients with cancer.

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Inhibitors of the heat shock protein 90: from cancer clinical trials to neurodegenerative diseases

Atlas of Genetics and Cytogenetics in Oncology and Haematology ◽

10.4267/2042/44950 ◽

2011 ◽

Author(s):

JF Peyrat ◽

S Messaoudi ◽

JD Brion ◽

M Alami

Keyword(s):

Clinical Trials ◽

Heat Shock ◽

Heat Shock Protein ◽

Neurodegenerative Diseases ◽

Heat Shock Protein 90 ◽

Cancer Clinical Trials

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Professional medical writing assistance in oncology clinical trials.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.e14088 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. e14088-e14088

Author(s):

Joseph Abi Jaoude ◽

Ramez Kouzy ◽

Walker Mainwaring ◽

Timothy Lin ◽

Austin B. Miller ◽

...

Keyword(s):

Clinical Trials ◽

Randomized Clinical Trials ◽

Scientific Communication ◽

Phase Iii ◽

Professional Writing ◽

Academic Publishing ◽

Cancer Clinical Trials ◽

Fda Approval ◽

English Speaking ◽

Medical Writers

e14088 Background: Academic publishing remains the cornerstone of biomedical research and scientific communication. Researchers often assign professional medical writers (PMWs) to craft publications, as these individuals may improve the overall writing quality and/or reduce time to publication. We sought to characterize the landscape of PMW utilization in phase III cancer clinical trials. Methods: We searched ClinicalTrials.gov for phase III randomized clinical trials between the years 2003 and 2018. Randomized multi-arm trials assessing a therapeutic intervention in cancer patients were included. After identifying the corresponding publications, we identified whether a PMW was involved in writing the manuscript based on author disclosures, along with any related funding information. Results: Six-hundred oncology RCTs with corresponding manuscripts were identified. In total, 260 (43.3%) trials used a PMW. Financial support to medical writers was largely provided by the industry (247/260, 95.0%). In multivariate analyses, PMW utilization was higher among industry-funded trials compared to non-industry-funded trials (OR: 14.2, p= 0.001). PMWs were used more frequently to report successful trials that met their primary endpoint (OR: 1.8, p= 0.03) but did not differ between English-speaking and non-English-speaking countries ( p= 0.19). Cooperative group trials used PMWs with less frequency compared to non-cooperative groups (OR 0.68, p < 0.001). PMWs were used more often in trials that led to subsequent drug FDA approval (69.6% vs 40.6% in trials that did not lead to subsequent FDA approval), but this association did not reach statistical significance in multivariate analysis ( p = 0.744). The use of PMWs has increased significantly over time (OR: 1.11/year, p =0.001). Conclusions: In this analysis, we show a strikingly high prevalence of PMW utilization in phase III oncology trials, with a vast majority of industry-supported studies using PMWs. We believe that professional writing assistance plays an important role in clear and efficient scientific communication. However, the disproportionate role of PMWs in reporting positive, industry-funded trials may represent a conflict of interest. We urge continued and increased reporting of utilization and funding of professional writing assistance in cancer clinical trials.

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