About

Alexander Lin, M.D., is the Morton M. Kligerman Professor of Radiation Oncology at the University of Pennsylvania and serves as the Executive Vice Chair in the Department of Radiation Oncology. He specializes in the multidisciplinary treatment of head and neck cancers, working collaboratively with departments such as Otorhinolaryngology, Medical Oncology, Pathology, Diagnostic Radiology, Oral Medicine, and Nuclear Medicine to improve cancer control, patient outcomes, and quality of life. Dr. Lin leads research programs focused on personalized approaches to head and neck cancer treatment, including studies on toxicity mitigation in HPV-associated oropharyngeal cancers and clinical trials investigating novel radiosensitizing agents targeting the tumor microenvironment. His research is funded by the National Cancer Institute and the National Institutes of Health. He completed his undergraduate studies at Yale University and his medical training at the University of Michigan Medical School, and is a board-certified radiation oncologist practicing at the University of Pennsylvania.

Research topics

• Internal medicine
• Medicine
• Computer Science
• Oncology
• Biology
• Physics
• Cancer research
• Microbiology
• Medical physics
• Nuclear engineering
• Engineering
• Surgery
• Nuclear physics
• Optics

Selected publications

• EE71 Cost-Effectiveness of Intensity-Modulated Proton Therapy (IMPT) for the Treatment of Head and Neck Oropharyngeal Carcinoma

  Value in Health · 2025-07-01

  article
  PublisherDOI

• Radiotherapy toxicities: mechanisms, management, and future directions

  The Lancet · 2025-01-01 · 100 citations

  reviewOpen accessSenior author
  PublisherOA PDFDOI

• International Expert-Based Consensus Definition, Classification Criteria, and Minimum Data Elements for Osteoradionecrosis of the Jaw: An Interdisciplinary Modified Delphi Study

  International Journal of Radiation Oncology*Biology*Physics · 2025-01-16 · 19 citations

  articleOpen access
  PublisherOA PDFDOI

• Utility and sensitivity of wett-SA53 to measure dysgeusia associated with talquetamab, a GPRC5D×CD3 bispecific antibody, in Relapsed/Refractory multiple myeloma: Preliminary data from the talisman study

  Blood · 2025-11-03

  articleOpen access

  Abstract Introduction: Talquetamab (Tal) is the first GPRC5D×CD3 bispecific antibody approved for the treatment of relapsed/refractory multiple myeloma (RRMM). Early onset of oral adverse events (AEs), including dysgeusia, have been reported with Tal and can impact patient (pt) quality of life. Further, the standard Common Terminology Criteria for Adverse Events (CTCAE) grading scale limits detailed assessment of dysgeusia. The TALISMAN study aims to better understand oral AEs, identify new tools for measurement, and investigate prophylactic interventions to prevent and/or limit the severity of Tal-related oral AEs. Here, we report preliminary data from the TALISMAN study. Methods:TALISMAN (NCT06500884) is an ongoing, phase 2, multicenter, global, randomized study. Eligible pts have RRMM and prior exposure to a proteasome inhibitor, immunomodulatory drug, and anti-CD38 antibody. At baseline, pts cannot have a “severe” score for dysgeusia per the Waterless Empirical Taste Test (WETT), a validated measure to identify various concentrations of taste stimuli. Pts are randomized to 1 experimental cohort (Tal plus an experimental prophylaxis) or the control cohort (Tal only). Experimental prophylaxes include dexamethasone [Dex] mouthwash, oral pregabalin, or clonazepam orally dissolving tablets. Pts receive prophylaxis starting 7 days before Tal step-up doses followed by Tal 0.8 mg/kg every other week. Tal dose may be reduced to every 4 weeks starting at cycle 5 for pts with a very good partial response or better (≥VGPR). The 4 co-primary endpoints are the rate of occurrence of dysgeusia, rate of occurrence of severe dysgeusia, time to first onset of severe dysgeusia, and rate of resolution/improvement of dysgeusia at 3 and 6 months, as defined by the WETT score. Key secondary endpoints include change from baseline in sense of smell, safety and efficacy, and patient-reported outcomes (PROs) such as the Scale of Subjective Total Taste Acuity (STTA), which assesses overall acuity of taste based on a 4-point scale (0 reflects no change and 4 represents almost complete loss of taste). Here, we report data from the control and Dex prophylaxis cohorts. Results: As of July 7, 2025, 17 pts (8 in control and 9 in Dex prophylaxis) were randomized. Median age was 62 years and 47% were male; 65% were White, 18% were Black, and 18% were Asian. Due to a pause in study enrollment for protocol updates, 2 groups are currently described: 5 initial pts (prior to enrollment pause; median follow-up [mFU], 240 days) and 12 additional pts (following enrollment pause) of which data are available for 8 pts (mFU, 19 days). Dysgeusia onset data were available through cycle 1 for the total 13 pts. By the WETT scale, scores tended to decline during cycle 1 with most pts (10/13) experiencing dysgeusia (WETT score ≤25th percentile) or severe dysgeusia (WETT score ≤10th percentile) by cycle 1 day 15, with majority (8/10) experiencing an immediate drop to severe dysgeusia; 2 pts had a step-wise drop from dysgeusia to severe dysgeusia by cycle 3. Further dysgeusia data were available only for the 5 initial pts: of 4/5 with dysgeusia, 2 had WETT scores that returned to normal (WETT score ≥26th percentile) and 2 had WETT scores that had not yet improved by cycle 8. In STTA analyses, preliminary data showed higher STTA scores, reflective of more severe perceived taste loss, during early cycles of Tal. By CTCAE grading, 3/5 pts had grade 1 dysgeusia and 1/5 pts had grade 2 dysgeusia; other oral AEs included xerostomia (2/5 pts, all grade 1) and oral mucositis (1/5 pts, grade 1). All initial pts (5/5) achieved a ≥VGPR by cycle 5 and remain on Tal at data cutoff. Additional pts and data including onset and resolution of dysgeusia, AEs, PROs, and biomarkers will be available at the time of presentation. Conclusions:In this randomized, phase 2 study utilizing the WETT SA-53 assessment tool for the first time in pts with MM,WETT scores appeared to be highly sensitive with the ability to objectively capture a broader spectrum of taste changes throughout Tal treatment compared with CTCAE grading. Preliminary data showed the WETT scale was able to detect dysgeusia, and importantly, objective improvements in dysgeusia by cycle 8. Results from this study will help characterize and guide management of dysgeusia associated with GPRC5D treatment and may establish the WETT assessment as an important objective tool for cancer agents impacting taste.

  PublisherOA PDFDOI

• Outcomes of <scp>HPV</scp> + Oropharyngeal Carcinoma of Unknown Primary Following Transoral Robotic Surgery

  The Laryngoscope · 2025-08-13 · 2 citations

  articleOpen access

  OBJECTIVES: Treatment of patients with head and neck squamous cell carcinoma of unknown primary (CUP) is challenging. Given the relative rarity of this condition and the recent use of primary transoral robotic surgery (TORS) in modern diagnostic and treatment algorithms, long-term oncologic outcomes are unclear. The objectives were to evaluate oncologic outcomes of patients treated with TORS for management of CUP. METHODS: This retrospective case series was conducted at a tertiary care academic medical center from 2010 to 2021. All patients with HPV-mediated CUP who underwent TORS-assisted endoscopy were included. CUP was defined as biopsy-proven squamous cell carcinoma in a cervical lymph node with uncertain primary location following standard-of-care clinical and radiologic assessment. Primary outcomes were recurrence-free survival and overall survival. Secondary outcomes included usage of radiation and chemotherapy. RESULTS: In total, 157 patients were included in the study. Median follow-up time was 62 months. Primary tumor was identified in 88% of patients. Surgery alone was performed in 21%, although adjuvant therapy was recommended but declined in 13%. Adjuvant radiation was completed in 46% and adjuvant chemoradiation in 33%. Two-thirds of patients avoided chemoradiation. Overall survival was 94% and recurrence-free survival was 92% at 5 years. CONCLUSION: In the largest reported experience to date of TORS-assisted management of CUP, we demonstrate that this approach facilitates a high rate of identification of occult mucosal malignancies and can eliminate the need for chemotherapy and potentially radiation therapy in select patients without compromising excellent oncologic and functional outcomes.

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• Chronic oral mucositis after head and neck radiation: a preliminary analysis of data from the OraRad study

  Oral Surgery Oral Medicine Oral Pathology and Oral Radiology · 2025-01-07

  article
  PublisherDOI

• Light-Controlled Synthetic Communication Networks via Paired Connexon Nanopores

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-04-11

  preprintOpen access

  Living cells employ dynamic networks for intercellular communication and cooperation, leading to tissue-wide activity. One emerging challenge in the field of bottom-up synthetic biology is emulating such sophisticated behaviors in liposome-based synthetic cells (SCs). Fabricating communication networks in lipid bilayer-based SCs remains a challenge as signaling molecules must transit through two consecutive membranes to transfer information between different SCs. Here, we address this obstacle by engineering connexin channels that directly connect the lumens of adhering SC membranes. We focus on orthogonal channel-forming connexins, namely connexin 43 and connexin 32, and re-design their channel activity to be UV- and near IR-responsive, respectively. By combining engineered connexins into a single SC assembly, we demonstrate orthogonal transfer of reactive signaling molecules between SCs, giving rise to unique reaction products and network states in a wavelength-dependent manner - an important step toward synthetic communication networks.

  PublisherOA PDFDOI

• Abstract LB434: Discovery and preclinical evaluation of ATM-5292: A potent and selective RNA targeting splice modulator for the treatment of non small cell lung cancer (NSCLC) and breast cancer, enabled by the PARSE™ machine learning platform

  Cancer Research · 2025-04-25

  article

  Abstract PARSE™, our proprietary machine learning (ML) platform, addresses critical challenges in RNA targeted drug discovery by accurately predicting structural and functional properties of RNA. Furthermore, the expansion of the platform with data relevant to drug discovery, has enabled target identification and prioritization of small molecules. Leveraging our platform, we have rapidly discovered ATM-5292, a dual small molecule inhibitor targeting two key oncogenes—FoxM1 and Myb. ATM-5292 is a first-in-class, orally bioavailable mRNA degrader that selectively targets both FoxM1 and Myb with equipotency. ATM-5292 potently modulates RNA splicing at low nanomolar concentrations, inducing inclusion of a cryptic exon in these two oncogene transcripts. This results in a premature stop codon within the mRNA, leading to degradation via nonsense-mediated decay. Consequently, protein levels of both targets are significantly reduced, directly correlating with splicing modulation. In vitro studies demonstrate that ATM-5292 has a direct correlation between splicing modulation, reduction of protein, and cytotoxicity in cancer cell lines. ATM-5292 demonstrates impressive efficacy in multiple cancer cell lines and patient-derived cancer cells including NSCLC, breast cancer, colorectal cancer, and ovarian cancer, consistent with its proposed mechanism of action. Comprehensive ADMET profiling confirms favorable drug-like properties, including significant oral bioavailability, dose-dependent exposure in preclinical species (mouse, rat, and dog), and pharmacokinetic properties supporting once-daily dosing. Notably, ATM-5292 demonstrates clear anti-tumor activity in a leukemia CDX model in immunocompromised mice, with dose-dependent effects. Preclinical non-GLP toxicology studies to evaluate the maximum tolerated dose (MTD) and dose range finding (DRF) in rats showed that therapeutic doses are well tolerated. These studies identified both effective and non-effective dose ranges, providing valuable data for dose selection in a subsequent 28-day GLP toxicity and pharmacokinetic study. In summary, ATM-5292 is a promising, first-in-class dual mRNA degrader with potent anti-tumor activity in preclinical models. It is well-positioned for further GLP toxicology studies and potential clinical development. Citation Format: Minna Bui, Praveen Kumar, Timothy Sproul, Michael J. Luzzio, Suparna Gupta, Debarati DasGupta, Kevin Patel, Meredith Corley, Ramya Rangan, Connor Stephens, Brandon Anderson, Alexander Lin, Yuzu Ido, Matias Kaplan, Ryan Chow, Arthur Chase, Brent Townshend, Stephan Eismann, Raphael Townshend, Manjunath Ramarao. Discovery and preclinical evaluation of ATM-5292: A potent and selective RNA targeting splice modulator for the treatment of non small cell lung cancer (NSCLC) and breast cancer, enabled by the PARSE™ machine learning platform [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB434.

  PublisherDOI

• Optimization and fabrication of a novel 3D‐printed variable density range modulation device for proton FLASH beams

  Medical Physics · 2025-09-22 · 2 citations

  articleOpen access

  BACKGROUND: For proton FLASH therapy, range-modulating devices are inserted in the beam path to create a spread-out-Bragg-peak (SOBP) for ultrafast delivery using a single energy pencil beam scanning technique. Current design typically consists of uniform density spikes with range modulation achieved by changing the area and height of the spikes, which has limited structural stability and modulation flexibility. PURPOSE: We present a new class of 3D-printed range-modulating devices for particle therapy with spatially modulated density. METHODS: PixelPrint technology (Laboratory for Advanced Computed Tomography Imaging, University of Pennsylvania, PA) was used to 3D-print the variable density range-modulator, by continuously varying the ratio of filament to air in each voxel. With specific thickness and spatial density modulation, SOBP of varying widths can be created. A calibration phantom was 3D printed and scanned by a dual-energy computed tomography (CT) scanner to characterize the physical and radiological properties of the PixelPrint technology. We developed an inverse optimization algorithm to generate the density map for producing SOBP from monoenergetic proton beam and verified by MCsquare (http://www.openmcsquare.org/), an open-source Monte Carlo (MC) simulation platform. The range modulation characteristics were measured using a multi-layer ionization chamber (MLIC) under monoenergetic proton field irradiation. RESULTS: The proposed optimization framework generated the density distributions for multiple SOBP widths. MC simulation verified the width and flatness of created SOBPs. The CT scan of a 3-cm SOBP modulator showed good fidelity of the desired density distribution, except for the highest density regions. MLIC measurements confirmed the accuracy of the produced SOBP with multiple proton beam energies. CONCLUSION: A novel variable density range-modulating device for proton therapy was successfully developed. These devices have the potential to be handled easily and significantly speed-up proton therapy treatment delivery.

  PublisherOA PDFDOI

• Abstract A002: Flash proton re-irradiation and hypofractionation alleviate radiation-induced toxicity of the head and neck tissues in mice

  Clinical Cancer Research · 2025-01-26

  article

  Abstract The effect of FLASH Proton Radiation therapy (F-PRT) in decreasing normal tissue toxicity while maintaining equal tumor control compared to Standard Proton Radiation therapy (S-PRT) has been previously investigated for head and neck tissues in mice using a single dose of either S-PRT/F-PRT. Here, we studied the effect of F-PRT following a hypo-fractionated regimen and in a re-irradiation setting. The head and neck area of C57Bl/6 mice was irradiated with a single dose of 12 Gy of F-PRT (128Gy/s) or S-PRT (0.95 Gy/s) and was followed with a hypo-fractionated re-irradiation scheme (6 Gy x 3). Mice with orthotopic tongue tumors were also irradiated with two different hypo-fractionated regimes of 8 Gy x 3 and 9 Gy x 3 respectively. Compared to the re-irradiation with S-PRT, F-PRT re-irradiated mice mitigate xerostomia by improving salivary flow. Histopathological analysis of the salivary gland showed increased acinar cell atrophy and individual cell death in the submandibular gland in mice re-irradiated with S-PRT compared to the ones re-irradiated with F-PRT. Re-irradiation with hypo-fractionated S-PRT showed a significant increase in the alveolar bone loss compared to F-PRT. Following irradiation with hypo-fractionated F-PRT mice with orthotopic tongue tumors significantly increases the overall survival compared to the ones irradiated with hypo-fractionated S-PRT. This study provides evidence of the sparing effect of F-PRT in minimizing radiation-induced head and neck tissue toxicity in a hypo-fractionated re-irradiation setting. The results support the efficacy of F-PRT for clinical application. Citation Format: Priyanka Chowdhury, George Morcos, Michele Kim, Yuewei Lin, Ling Qin, James Metz, Alexander Lin, Costas Koumenis. Flash proton re-irradiation and hypofractionation alleviate radiation-induced toxicity of the head and neck tissues in mice. [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Translating Targeted Therapies in Combination with Radiotherapy; 2025 Jan 26-29; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(2_Suppl):Abstract nr A002.

  PublisherDOI

Frequent coauthors

• John N. Lukens

  University of Pennsylvania

  74 shared

• Samuel Swisher‐McClure

  59 shared

• Roger B. Cohen

  University of Pennsylvania

  47 shared

• Bert W. O’Malley

  Baylor College of Medicine

  40 shared

• Gregory S. Weinstein

  University of Pennsylvania

  34 shared

• Ara A. Chalian

  University of Pennsylvania

  31 shared

• Jason G. Newman

  Medical University of South Carolina

  31 shared

• James M. Metz

  28 shared

Education

• B.A., Molecular Biophysics and Biochemistry

  Yale University

  1998

• M.D., Medicine

  University of Michigan Medical School

  2002

• Other, Certificate in Financial Accounting

  Harvard Business School Online

  2019