Conducting a Virtual Clinical Trial in HER2-Negative Breast Cancer Using a Quantitative Systems Pharmacology Model With an Epigenetic Modulator and Immune Checkpoint Inhibitors

Frontiers in Bioengineering and Biotechnology
Hanwen WangAleksander S Popel

Abstract

The survival rate of patients with breast cancer has been improved by immune checkpoint blockade therapies, and the efficacy of their combinations with epigenetic modulators has shown promising results in preclinical studies. In this prospective study, we propose an ordinary differential equation (ODE)-based quantitative systems pharmacology (QSP) model to conduct an in silico virtual clinical trial and analyze potential predictive biomarkers to improve the anti-tumor response in HER2-negative breast cancer. The model is comprised of four compartments: central, peripheral, tumor, and tumor-draining lymph node, and describes immune activation, suppression, T cell trafficking, and pharmacokinetics and pharmacodynamics (PK/PD) of the therapeutic agents. We implement theoretical mechanisms of action for checkpoint inhibitors and the epigenetic modulator based on preclinical studies to investigate their effects on anti-tumor response. According to model-based simulations, we confirm the synergistic effect of the epigenetic modulator and that pre-treatment tumor mutational burden, tumor-infiltrating effector T cell (Teff) density, and Teff to regulatory T cell (Treg) ratio are significantly higher in responders, which can be potentia...Continue Reading

References

Apr 14, 1999·Proceedings of the National Academy of Sciences of the United States of America·A SaitoO Nakanishi
Apr 27, 2005·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Qin C RyanEdward A Sausville
Jul 22, 2005·The Journal of Immunology : Official Journal of the American Association of Immunologists·Andreas JanssonPatric Nilsson
Sep 19, 2007·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Shivaani KummarAnthony J Murgo
Jun 24, 2008·Journal of Theoretical Biology·Simeone MarinoDenise E Kirschner
Jun 27, 2008·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Lia GoreS Gail Eckhardt
Aug 30, 2008·Molecular Cancer Therapeutics·John O RichardsJohn R Desjarlais
Dec 23, 2008·European Journal of Cancer : Official Journal for European Organization for Research and Treatment of Cancer (EORTC) [and] European Association for Cancer Research (EACR)·E A EisenhauerJ Verweij
Jul 23, 2013·Methods : a Companion to Methods in Enzymology·Brian D HarmsAlexey A Lugovskoy
Jan 18, 2014·British Journal of Clinical Pharmacology·Yan FengAmit Roy
Jul 30, 2014·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Sylvia AdamsSunil S Badve
Jul 30, 2014·Proceedings of the National Academy of Sciences of the United States of America·KiBem KimShibin Zhou
Aug 26, 2014·Nature Reviews. Immunology·Melissa LeverOmer Dushek
Apr 29, 2015·Proceedings of the National Academy of Sciences of the United States of America·Emanuela RomanoDaniel E Speiser
Feb 10, 2016·Trends in Immunology·Vinit KumarDmitry I Gabrilovich
Apr 14, 2016·CPT: Pharmacometrics & Systems Pharmacology·R J AllenC J Musante
May 31, 2016·Nature Genetics·Bo LiX Shirley Liu
Dec 27, 2016·CPT: Pharmacometrics & Systems Pharmacology·G BajajY Feng
Jun 14, 2017·Current Opinion in Pharmacology·Stuart J GallagherPeter Hersey
Jun 15, 2017·Molecular Oncology·Stéphane TerrySalem Chouaib
Jul 13, 2017·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Ashley OrillionRoberto Pili
Aug 13, 2017·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Leisha A Emens
Sep 25, 2017·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Roberto PiliMichael A Carducci
Dec 21, 2017·The New England Journal of Medicine·Mark YarchoanElizabeth M Jaffee
Jan 20, 2018·CPT: Pharmacometrics & Systems Pharmacology·Marjoleen J M A NijsenMary E Spilker
Mar 27, 2018·Cancer Cell·Frederick Arce VargasSergio A Quezada
Mar 28, 2018·Proceedings of the National Academy of Sciences of the United States of America·Jessica R IngramMichael Dougan
Mar 28, 2018·Asian Pacific Journal of Cancer Prevention : APJCP·Moureq R AlotaibiOthman A Al-Shabanah
Mar 30, 2018·Breast Cancer Research and Treatment·Pranabananda DuttaJaydutt V Vadgama
Jun 15, 2018·Progress in Biophysics and Molecular Biology·Theodore R RiegerCynthia J Musante
Jul 18, 2018·Cancer Immunology Research·Genevieve P HartleySteven W Dow

❮ Previous
Next ❯

Citations

Jul 21, 2020·Clinical Pharmacology and Therapeutics·Vijayalakshmi ChelliahAndrzej M Kierzek
Jul 4, 2020·CPT: Pharmacometrics & Systems Pharmacology·Richard J SovéAleksander S Popel
Jun 14, 2020·The AAPS Journal·Huilin MaAleksander S Popel
Dec 17, 2020·Bioinformatics·S SinisiB Leeners
Aug 11, 2021·Pharmaceutics·Aymara Sancho-AraizIñaki F Trocóniz
Aug 10, 2021·Frontiers in Bioengineering and Biotechnology·Virginia CazzagonFrancesco Gonella

❮ Previous
Next ❯

Methods Mentioned

BETA
transgenic

Clinical Trials Mentioned

NCT02453620
NCT02115282

Software Mentioned

ggpubr
MATLAB
SimBiology
RStudio
MATLAB Global Optimization Toolbox

Related Concepts

Related Feeds

Breast Cancer Triple-N

Breast cancer cells have receptors for estrogen, progesterone, HER2 receptors (also called ERBB2). Triple-negative breast cancers do not have any of these receptors. Here are the latest discoveries pertaining to triple-negative breast cancers.

Cancer Vaccines

Cancer vaccines are vaccines that either treat existing cancer or prevent development of a cancer.