Jacob Miller, MD
Associate Staff
Location: Cleveland Clinic Main Campus
Research
Chronic viral infections cause approximately 20% of solid tumors worldwide. Lifelong Human Papillomavirus (HPV) and Epstein-Barr Virus (EBV) infection are responsible for the vast majority of cervical, oropharyngeal, nasopharyngeal, and anal cancers. Although HPV vaccination exists, millions of unvaccinated adults older than 30 are chronically infected with HPV and will go on to develop these tumors decades later. In contrast, more than 90% of adults worldwide are chronically-infected with EBV, for which there exists no vaccination or treatment.
Viral-based screening methods for these cancers are either unavailable or not routinely performed in North America. As a result, thousands of healthy individuals with chronic viral infection will go on to develop these life-threatening tumors and suffer from the long-term consequences of surgery, radiotherapy, and chemotherapy. The Miller lab studies these tumors to develop better tests and screening programs for use in early cancer detection and biomarker-directed treatment.
Biography
Dr. Jacob Miller is a radiation oncologist specializing in the treatment of head/neck and gastrointestinal cancers. After his medical education at the Cleveland Clinic Lerner College of Medicine, he completed his radiation oncology residency training at Stanford University. During his training, he developed molecular diagnostics for cell-free Epstein-Barr Viral genotyping and quantitation for use in nasopharyngeal carcinoma early detection, pre-treatment prognostication, and non-invasive surveillance.
After returning to the Cleveland Clinic, Dr. Miller joined the Department of Radiation Oncology and the Center for Immunotherapy and Precision Immuno-Oncology (CITI) as Associate Staff. He conducts translational cancer research within the CITI Discovery Lab. His current research interests include cell-free HPV/EBV detection, genotyping, and serology for use in pre-treatment prognostication, risk-adapted therapy, and population-level cancer screening.
Education & Professional Highlights
Appointed
2022
Education & Fellowships
Residency - Stanford Health Care
Radiation Oncology
Stanford, CA USA
2022
Internship - Kaiser Permanente San Francisco
Internal Medicine
San Francisco, CA USA
2018
Medical Education - Cleveland Clinic Lerner College of Medicine
Cleveland, OH USA
2017
Undergraduate - Case Western Reserve University
Chemistry
Cleveland, OH USA
2012
Certifications
- Radiology - Radiation Oncology
Awards & Honors
- Howard Hughes Medical Institute Research Fellowship
- W.R. Veazey Prize for Excellence in Physical Chemistry
- Case Comprehensive Cancer Center Trainee Award for Cancer Research
- American Brain Tumor Association Lucien J. Rubinstein Award
- Intern of the Year, Kaiser Permanente San Francisco Department of Internal Medicine
- American Society for Radiation Oncology Resident Seed Grant Awardee
- RSNA Roentgen Resident/Fellow Research Award
Memberships
- American Society for Radiation Oncology
- American College of Radiology
- American College of Radiation Oncology
- American Association for Cancer Research
Research
Overview
The Miller Lab focuses on advancing early cancer detection and biomarker-driven treatment strategies for head and neck cancers, particularly on tumors associated with chronic viral infections such as HPV and EBV. Our research integrates molecular diagnostics, liquid biopsy technologies, and targeted molecular assays with the goal of improving prognostication, risk-adapted therapy, and non-invasive disease monitoring. By leveraging approaches such as targeted methylation sequencing and multiplexed cell-free DNA detection, we aim to develop noninvasive, cost-effective tools for early detection and real-time assessment of treatment response while continuing to expand the clinical applications of cfDNA-based diagnostics.
Ongoing Projects
- Plasma cfDNA Methylation as a Biomarker of Tumor Hypoxia in HNSCC: Tumor hypoxia is a key predictor of poor response to therapy in head and neck squamous cell carcinoma (HNSCC), and imaging-based detection methods are not widely available and do not provide molecular insights. To address this, the Miller Lab is working towards developing a hybrid-capture bisulfite sequencing assay that targets differentially methylated regions linked to hypoxia, HPV dysplasia, and key tumor-associated pathways. By profiling these differentially methylated regions in cfDNA from patients with HPV-positive and HPV-negative HNSCC, we aim to enable the dynamic monitoring of these methylation signatures, which could serve as a surrogate for bulk tumor gene expression, allow for noninvasive inference of intratumoral hypoxia, and give us the ability to assess its role in treatment response and resistance.
Our Team
Selected Publications
Miller, J.A.; Bennett, E.E.; Xiao, R.; Kotecha, R.; Chao, S.T.; Vogelbaum, M.A.; Barnett, G.H.; Angelov, L.; Murphy, E.S.; Yu, J.S.; Ahluwalia, M.S.; Suh, J.H.; Mohammadi, A.M. “Association between Radiation Necrosis and Tumor Biology following Stereotactic Radiosurgery for Brain Metastasis.” International Journal of Radiation Oncology, Biology, and Physics. 2016 Dec 1;96(5):1060-1069. PMID: 27742540.
Miller, J.A.; Kotecha, R.; Ahluwalia, M.S.; Mohammadi, A.M.; Chao, S.T.; Barnett, G.H.; Murphy, E.S.; Vogelbaum, M.A.; Angelov, L.; Peereboom, D.M.; Suh, J.H. “Overall Survival and the Response to Radiation Therapy among Molecular Subtypes of Breast Cancer Brain Metastases Treated with Targeted Therapies.” Cancer. 2017 Jun 15;123(12):2283-2293. PMID: 28192598.
Kim, J.M.; Miller, J.A.; Kotecha, R.; Xiao R.; Juloori, A.; Ward, M.C.; Ahluwalia, M.; Mohammadi, A.M.; Peereboom, D.M.; Murphy, E.S.; Suh, J.H.; Barnett, G.H.; Vogelbaum, M.A.; Angelov, L.; Stevens, G.H.; Chao, S.T. “The Risk of Radiation Necrosis following Stereotactic Radiosurgery with Concurrent Systemic Therapies.” The Journal of Neuro-Oncology. 2017 Jun;133(2):357-368. PMID: 28434110.
Kotecha, R.; Kim, J.M.; Miller, J.A.; Juloori, A.; Chao, S.T.; Murphy, E.S.; Peereboom, D.M.; Mohammadi, A.M.; Barnett, G.H.; Vogelbaum, M.A.; Angelov, L.; Suh, J.H.; Ahluwalia, M.S. “The Impact of Sequencing PD-1/PD-L1 Inhibitors and Stereotactic Radiosurgery for Patients with Brain Metastasis.” Neuro-Oncology. 2019 Feb 23;21(8):1060-1068. PMID: 30796838.
Miller, J.A.; Wang, H.; Chang, D.T.; Pollom, E.L. “Cost-Effectiveness and Quality-Adjusted Survival of Watch-and-Wait after Complete Response to Chemoradiotherapy for Rectal Cancer.” Journal of the National Cancer Institute. 2020 Aug 1;112(8):792-801. PMID: 31930400.
Wang, H.; Hogan, C; Miller, J.A.; Sahoo, M.; Huang, C.H.; Mfuh, K.; Sibai, M.; Zehnder, J.; Hickey, B.; Sinnott-Armstrong, N.; Pinsky, B. “Performance of Nucleic Acid Amplification Tests for Detection of SARS-CoV-2 in Prospectively Pooled Specimens.” Emerging Infectious Diseases. 2021 Jan;27(1):92-103. PMID: 33183494.
Verghese, M.; Jiang, B.; Iwai, N.; Mar, M.; Sahoo, M.; Yamamoto, F.; Mfuh, K.; Miller, J.A.; Wang, H.; Zehnder, J.; Pinsky, B.A. “Identification of a SARS-CoV-2 Variant with L452R and E484Q Neutralization Resistance Mutations." Journal of Clinical Microbiology. 2021 Jun 18;59(7):e0074121. PMID: 33952596.
Wang, H.; Miller, J.A.; Verghese, M.; Sibai, M.; Solis, D.; Mfuh, K.O.; Jiang, B.; Iwai, N.; Mar, M.; Huang, C.; Yamamoto, F.; Sahoo, M.K.; Zehnder, J.; Pinsky, B.A. “Multiplex SARS-CoV-2 Genotyping PCR for Population-Level Variant Screening and Epidemiologic Surveillance.” Journal of Clinical Microbiology. 2021 Jul 19;59(8):e0085921. PMID: 34037430.
Miller, J.A.; Le, Q-T.; Pinsky, B.A.; Wang, H. “Cost-Effectiveness of Nasopharyngeal Carcinoma Screening with Epstein-Barr Virus Polymerase Chain Reaction or Serology in High-Incidence Populations Worldwide.” Journal of the National Cancer Institute. 2021 Jul 1;113(7):852-862. PMID: 33351145.
Jacobson, K.B.; Pinsky, B.A.; Rath, M.E.M.; Wang, H.; Miller, J.A.; Skhiri, M.; Shepard, J.; Mathew, R.; Lee, G.; Bohman, B.; Parsonnet, J.; Holubar, M. “Post-vaccination SARS-CoV-2 Infections and Incidence of Presumptive B.1.427/B.1.429 Variant Among Healthcare Personnel at a Northern California Academic Medical Center.” Clinical Infectious Diseases. 2021 Sep 1;111(1):29-35. PMID: 34137815.
Miller, J.A.; Toesca, D.A.S.; Baclay, J.R.M.; Pollom, E.L.; Chang, D.T. “Pancreatic Stereotactic Body Radiation Therapy with or without Hypofractionated Elective Nodal Irradiation.” Int J Radiat Oncol Biol Phys. 2022 Jan1;112(1):131-142. PMID: 34348171.
Dashdorj, N.J.; Wirz, O.F.; Röltgen, K.; Haraguchi, E.; Buzzanco, A.S. 3rd; Sibai, M.; Wang, H.; Miller, J.A.; Solis, D.; Sahoo, M.K.; Arunachalam, P.S.; Lee, A.S.; Shah, M.M.; Liu, J.; Byambabaatar, S.; BatUlzii, P.; Enkhbat, A.; Batbold, E.; Zulkhuu, D.; Ochirsum, B.; Khurelsukh, T.; Dalantai, G.; Burged, N.; Baatarsuren, U.; Ariungerel, N.; Oidovsambuu, O.; Bungert, A.S.; Genden, Z.; Yagaanbuyant, D.; Mordorj, A.; Pulendran, B.; Chinthrajah, S.; Nadeau, K.C.; Jardetzky, T.; Wilbur, J.L.; Wohlstadter, J.N.; Sigal, G.B.; Pinsky, B.A.; Boyd, S.D.; Dashdorj, N.D. “Direct Comparison of Antibody Responses to Four SARS-CoV-2 Vaccines in Mongolia.” Cell Host Microbe. 2021 Dec 8;29(12):1738-1743. PMID: 34861167.
Ward, M.C.; Miller, J.A., Walker, G.V.; Moeller, B.J.; Koyfman, S.A.; Shah, C. "The Economic Impact of Circulating Tumor-Tissue Modified HPV DNA for the Post-Treatment Surveillance of HPV-Driven Oropharyngeal Cancer: A Simulation". Oral Oncol. 2022 Mar;126:105721. PMID: 35077916.
Miller, J.A.; Moradi, F.; Sundaram, V.; Liang, R.; Zhang, C.; Nguyen, N.K.; Akhtar, F.; Liu, Y.; Ren, Y.; Harandi, N.; Weng, Y.; Pollom, E.; Colevas, A.D.; Divi, V.; Holsinger, F.C.; Beadle, B.M.; Le, Q-T.; Gensheimer, M.F. "Post-Treatment FDG-PET/CT Hopkins Criteria Predict Locoregional Recurrence after Definitive Radiotherapy for Oropharyngeal Squamous Cell Carcinoma." Head & Neck. 2022. PMID: 35920790.
Miller, J.A.; Sahoo, M.K.; Yamamoto, F.; Huang, C.; Wang, H.; Zehnder, J.; Le, Q-T.; Pinsky, B.A. "Multiplex Epstein-Barr Virus BALF2 Genotyping Detects High-Risk Variants in Plasma for Population Screening of Nasopharyngeal Carcinoma." Molecular Cancer. 2022. PMID: 35902864.
Miller, J. A.; Liu, Z.; Pinsky, B. A.; Le, Q. T.; Li, T.; Yu, K. J.; Hildesheim, A.; Cao, S. M.; "Optimization and Local Cost-Effectiveness of Nasopharyngeal Carcinoma Screening Strategies in Southern China: Secondary Analysis of the Guangdong Randomized Trial." Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology. 2024. PMID: 38695706.
Clark, P. E.; Taparra, K.; & Miller, J. A.; "Identification of High-Incidence Populations in the United States for anti-Epstein Barr Virus Serologic Screening for Nasopharyngeal Carcinoma." Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology. 2024. PMID: 39361358.
Clark P., Karasik N., Campbell S.R., Woody N.M., Ku J.A., Silver N., Bottalico D., Prendes B.L., Lamarre E.D., Scharpf J., Sussman T.A., Geiger J.L., Wang H., Chan T.A., Koyfman S.A., Miller J.A. Highly-multiplex detection of plasma cell-free human papillomavirus-16 DNA in oropharyngeal carcinoma. J Clin Virol. 2025 Feb;176:105760. doi: 10.1016/j.jcv.2025.105760. Epub 2025 Jan 2. PMID: 39793474.