Rational selection of biomarker driven therapies for gynecologic cancers: The more we know, the more we know we don't know

Liu, Joyce F.; Westin, Shannon N.

doi:10.1016/j.ygyno.2016.01.003

Cited by 12 publications

(5 citation statements)

References 93 publications

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“…Despite the use of screening programs and the improvements in therapeutic approaches, CC remains the fourth most lethal cancer among women worldwide ( 1 , 2 ). In an effort to improve the efficacy of antitumor therapies, numerous current medical strategies are aimed at designing novel inhibitors of the relevant molecular pathways ( 30 ). In this context, the current study focused on investigating the antitumor effects of HIV-PIs, a class of drugs that reduce the incidence and/or promote the regression of AIDS-associated cancers, independently of their anti-HIV or immune-reconstituting activities ( 12 – 21 ).…”

Section: Discussionmentioning

confidence: 99%

The HIV-protease inhibitor saquinavir reduces proliferation, invasion and clonogenicity in cervical cancer cell lines

et al. 2016

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Innovative therapies in cervical cancer (CC) remain a priority. Recent data indicate that human immunodeficiency virus (HIV)-protease inhibitors used in highly active antiretroviral therapy can exert direct antitumor activities also in HIV-free preclinical and clinical models. The aim of the present study was to evaluate the antineoplastic effects of various HIV-protease inhibitors (indinavir, ritonavir and saquinavir) on primary and established CC cell lines. Two CC cell lines established in our laboratory and four commercially available CC cell lines were treated with indinavir, ritonavir and saquinavir at different concentrations and for different times. Proliferation, clonogenicity and radiosensitivity were evaluated by crystal violet staining. Proteasomal activities were assessed using a cell-based assay and immunoblotting. Cell cycle was analyzed by propidium iodide staining and flow cytometric analysis. Invasion was tested with Matrigel chambers. A t-test for paired samples was used for statistical analysis. In all cell lines, saquinavir was more effective than ritonavir in reducing cell proliferation and inhibiting proteasomal activities (P≤0.05). Conversely, indinavir exerted a negligible effect. The saquinavir concentrations required to modulate the proteasome activities were higher than those observed to be effective in inhibiting cell proliferation. In HeLa cells, saquinavir was strongly effective in inhibiting cell invasion and clonogenicity (P≤0.05) at concentrations much lower than those required to perturb proteasomal activities. Saquinavir did not contribute to increase the sensitivity of HeLa cells to X-rays. In conclusion, the present results demonstrate that saquinavir is able to significantly reduce cell proliferation, cell invasion and clonogenicity in a proteasome-independent manner in in vitro models of CC, and suggest that saquinavir could be a promising CC therapeutic agent.

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Section: Discussionmentioning

confidence: 99%

The HIV-protease inhibitor saquinavir reduces proliferation, invasion and clonogenicity in cervical cancer cell lines

et al. 2016

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“…This biomarker-driven therapeutic strategy can be applied to treat ovarian tumours, which are characterised by differentially expressing tumour-antigens [ 14 ]. However, there is an increasing need to enhance selection of early-stage molecules to mitigate late-stage failures.…”

Section: Introductionmentioning

confidence: 99%

Elucidating Novel Targets for Ovarian Cancer Antibody–Drug Conjugate Development: Integrating In Silico Prediction and Surface Plasmon Resonance to Identify Targets with Enhanced Antibody Internalization Capacity

Onyido,

James,

Garcia-Parra

et al. 2023

Antibodies

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Antibody–drug conjugates (ADCs) constitute a rapidly expanding category of biopharmaceuticals that are reshaping the landscape of targeted chemotherapy. The meticulous process of selecting therapeutic targets, aided by specific monoclonal antibodies’ high specificity for binding to designated antigenic epitopes, is pivotal in ADC research and development. Despite ADCs’ intrinsic ability to differentiate between healthy and cancerous cells, developmental challenges persist. In this study, we present a rationalized pipeline encompassing the initial phases of the ADC development, including target identification and validation. Leveraging an in-house, computationally constructed ADC target database, termed ADC Target Vault, we identified a set of novel ovarian cancer targets. We effectively demonstrate the efficacy of Surface Plasmon Resonance (SPR) technology and in vitro models as predictive tools, expediting the selection and validation of targets as ADC candidates for ovarian cancer therapy. Our analysis reveals three novel robust antibody/target pairs with strong binding and favourable antibody internalization rates in both wild-type and cisplatin-resistant ovarian cancer cell lines. This approach enhances ADC development and offers a comprehensive method for assessing target/antibody combinations and pre-payload conjugation biological activity. Additionally, the strategy establishes a robust platform for high-throughput screening of potential ovarian cancer ADC targets, an approach that is equally applicable to other cancer types.

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“…21 Targeting single pathways may be insufficient given tumor heterogeneity, escape pathways, and low response rates. 22 Evidence is emerging that patients may benefit most from an N-of-one approach, examining all available NGS to determine a customized, often multiagent, treatment-to-target driver alterations, taking into context biomarkers of resistance, drug interactions, and clinical history. 6,7,[23][24][25][26] Evidence using multiple agents to target various alterations in an individual's gynecologic or breast cancer is limited, 5,27 likely due at least in part to the complexity of managing combination therapy dosing and treatment-related adverse events.…”

Section: Introductionmentioning

confidence: 99%

Real-World Data From a Molecular Tumor Board: Improved Outcomes in Breast and Gynecologic Cancers Patients With Precision Medicine

Charo

Eskander

Sicklick

et al. 2022

JCO Precision Oncology

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PURPOSE Next-generation sequencing is increasingly used in gynecologic and breast cancers. Multidisciplinary Molecular Tumor Board (MTB) may guide matched therapy; however, outcome data are limited. We evaluate the effect of the degree of matching of tumors to treatment as well as compliance to MTB recommendations on outcomes. METHODS Overall, 164 patients with consecutive gynecologic and breast cancers presented at MTB were assessed for clinicopathologic data, next-generation sequencing results, MTB recommendations, therapy received, and outcomes. Matching score (MS), defined as percentage of alterations targeted by treatment over total pathogenic alterations, and compliance to MTB recommendations were analyzed in context of oncologic outcomes. RESULTS Altogether, 113 women were evaluable for treatment after MTB; 54% received matched therapy. Patients with MS ≥ 40% had higher overall response rate (30.8% v 7.1%; P = .001), progression-free survival (PFS; hazard ratio [HR] 0.51; 95% CI, 0.31 to 0.85; P = .002), and a trend toward improved overall survival (HR 0.64; 95% CI, 0.34 to 1.25; P = .082) in univariate analysis. The PFS advantage remained significant in multivariate analysis (HR 0.5; 95% CI, 0.3 to 0.8; P = .006). Higher MTB recommendation compliance was significantly associated with improved median PFS (9.0 months for complete; 6.0 months for partial; 4.0 months for no compliance; P = .004) and overall survival (17.1 months complete; 17.8 months partial; 10.8 months none; P = .046). Completely MTB-compliant patients had higher MS ( P < .001). In multivariate analysis comparing all versus none MTB compliance, overall response (HR 9.5; 95% CI, 2.6 to 35.0; P = .001) and clinical benefit (HR 8.8; 95% CI, 2.4 to 33.2; P = .001) rates were significantly improved with higher compliance. CONCLUSION Compliance to MTB recommendations resulted in higher degrees of matched therapy and correlates with improved outcomes in patients with gynecologic and breast cancers.

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Rational selection of biomarker driven therapies for gynecologic cancers: The more we know, the more we know we don't know

Cited by 12 publications

References 93 publications

The HIV-protease inhibitor saquinavir reduces proliferation, invasion and clonogenicity in cervical cancer cell lines

The HIV-protease inhibitor saquinavir reduces proliferation, invasion and clonogenicity in cervical cancer cell lines

Elucidating Novel Targets for Ovarian Cancer Antibody–Drug Conjugate Development: Integrating In Silico Prediction and Surface Plasmon Resonance to Identify Targets with Enhanced Antibody Internalization Capacity

Real-World Data From a Molecular Tumor Board: Improved Outcomes in Breast and Gynecologic Cancers Patients With Precision Medicine

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