About

Constantinos Koumenis, Ph.D., is the Richard H. Chamberlain Professor of Radiation Oncology at the University of Pennsylvania's Perelman School of Medicine. His research focuses on understanding the tumor microenvironment, tumor metabolism, and the integrated stress response, with an emphasis on developing novel, physiologically relevant animal models of incidental radiation damage. He employs innovative radiation delivery technologies such as FLASH radiotherapy to identify biomarkers of response and improve the therapeutic window of radiation therapy. His laboratory investigates how components of the microenvironment, like hypoxia and low nutrient availability, interact with cellular survival and apoptotic pathways to produce resistant tumor phenotypes. Additionally, he works on increasing the efficacy of ionizing radiation by screening for and developing radiation sensitizers, including the use of biocompatible nanoparticles. Dr. Koumenis has contributed to advancing the understanding of radiation biology and therapy, with a particular interest in mechanisms that regulate tumor resistance and response to treatment.

Research topics

• Computer Science
• Medicine
• Artificial Intelligence
• Cancer research
• Biology
• Internal medicine
• Machine Learning
• Pathology
• Oncology
• Bioinformatics
• Computational biology
• Nuclear engineering
• Genetics
• Physics
• Cell biology
• Biochemistry
• Optics
• Medical physics
• Nuclear physics
• Engineering

Selected publications

• Development and Evaluation of a Proton Irradiation Setup for Radiobiological Studies Using Low-Energy Protons with a Polyenergetic Spectrum (0–5.5 MeV, Mean 4.1 MeV)

  Radiation · 2026-02-21

  articleOpen access

  Proton therapy offers superior dose localization, yet the biological effects of low-energy protons relevant to superficial tissues remain underexplored. We report the design and validation of a proton irradiation setup developed at the Tandem Accelerator of NCSR “Demokritos” for controlled radiobiological experiments. Monte Carlo simulations using Geant4 and Monte Carlo Damage Simulation (MCDS—Monte Carlo Damage Simulation) were used to determine proton energy spectra, linear energy transfer (LET), and predicted DNA damage yields. A single layer (15–20 μm in thickness) of human keratinocytes (HaCaT) was irradiated at doses from 0.65 to 3.65 Gy, and γ-H2AX foci were quantified as markers of tracks including one or more DNA double-strand breaks. The system achieved a uniform dose rate of 0.37 Gy/min, as calculated with Geant4, with a mean proton energy of 4.1 MeV (LET ≈ 8 keV/μm). A strong correlation (R2 = 0.93) was observed between proton dose and γH2AX foci per nucleus (~10 foci/Gy), reflecting damage-inducing proton tracks rather than individual DNA double-strand breaks. At higher doses, an increased fraction of cells exhibited pan-nuclear γH2AX staining, characterized by a diffuse γH2AX signal throughout the nucleus and commonly associated with extensive or clustered DNA damage and global chromatin phosphorylation. These responses are consistent with the well-established dense ionization patterns produced by low-energy protons, as indicated by the LET spectrum and supported by MCDS-predicted clustered damage yields. While the γH2AX assay does not directly resolve simple versus complex DNA lesions, the agreement between Monte Carlo modeling and the observed cellular stress responses indicates that the irradiation platform reliably reproduces the expected biological signatures of low-energy proton exposure. Consequently, the developed system provides a robust experimental tool for systematic investigations of cellular radiosensitivity and radiotoxicity, with potential applications in skin dosimetry and radioprotection.

  PublisherOA PDFDOI

• Radiobiological and Clinical Advantages of Proton Therapy in Modern Cancer Treatment

  Repository KITopen (Karlsruhe Institute of Technology) · 2026-01-01

  articleOpen access

  Background/Objectives: Proton therapy has emerged as an advanced radiotherapy modality due to its unique physical dose distribution and its distinct radiobiological properties. The finite range of protons in tissue enables highly conformal dose delivery with minimal exit dose, significantly reducing irradiation of surrounding normal tissues compared to photon-based radiotherapy. Beyond these physical advantages, proton beams exhibit a spatially varying linear energy transfer that increases toward the distal edge of the spread-out Bragg peak, leading to clustered and complex DNA damage that is more difficult for cancer cells to repair. Methods: This review integrates experimental, computational, and clinical evidence to examine how proton-induced DNA damage, relative biological effectiveness, oxygen effects, and non-targeted responses contribute to tumor control and normal tissue sparing. Results: Comparative analyses with photon intensity-modulated radiotherapy demonstrate consistent reductions in acute and late toxicities across multiple tumor sites, particularly in pediatric patients and in tumors located near critical organs. The review also discusses emerging technologies, including pencil beam scanning, image-guided and adaptive proton therapy, compact accelerator systems, and ultra-high dose rate FLASH proton therapy, which collectively aim to enhance treatment precision, biological effectiveness, and accessibility. Conclusions: Together, these developments support proton therapy as a rapidly evolving modality with significant potential to improve therapeutic outcomes in modern oncology.

  PublisherDOI

• SPTBN2 promotes an immunosuppressive tumor microenvironment and cross-resistance to anti-cancer therapies

  bioRxiv (Cold Spring Harbor Laboratory) · 2026-04-01

  articleOpen access

  Immunosuppressive tumor microenvironment (TME) inactivates CD8+ cytotoxic lymphocytes (CTLs). Here, we identify SPTBN2 spectrin as a key immunosuppressive regulator induced in CTLs in response to nutritional deficit. In human pancreatic and colorectal cancers, SPTBN2 expression negatively correlated with CTL infiltration and patients' survival. In TME of mouse pancreatic and colorectal adenocarcinomas, SPTBN2 inactivated intratumoral CTLs, stimulated tumor growth and conferred cross-resistance to anti-cancer therapies. SPTBN2 knockout protected CAR T-cells from trogocytosis and increased their memory state. SPTBN2 maintained levels of cell surface proteins such as BTLA that undermine CAR T-cell cytotoxicity and promote exhaustion. Re-expression of BTLA largely reversed phenotypes in SPTBN2-deficient CAR T-cells. In manufactured CAR T cells, SPTBN2 was associated with their clinical failure in pediatric patients with leukemia. Accordingly, ablation of SPTBN2 in CAR T-cells increased their cytotoxicity, in vivo persistence and therapeutic effects indicating that SPTBN2 can be targeted to increase the efficacy of anti-cancer therapies.

  PublisherOA PDFDOI

• FLASH Particle Radiotherapy

  The Cancer Journal · 2026-03-01

  article

  FLASH radiotherapy is an emerging treatment modality characterized by the ultrahigh dose rate delivery of radiation, which has demonstrated the potential to significantly reduce normal tissue toxicity while maintaining tumor control. In cancers traditionally managed with radiotherapy, this approach could improve the therapeutic ratio by mitigating severe side effects associated with current techniques. The integration of particle therapy-such as protons or heavier ions-with FLASH dose rates offers unique physical and biological advantages, including enhanced normal tissue sparing and the possibility of safe dose escalation. Clinical implementation will require a deeper understanding of the mechanistic biological underpinnings of the FLASH effect, alongside advancements in beam delivery systems capable of achieving FLASH dose rates, rigorous quality assurance protocols, and adaptive strategies to accommodate anatomic changes during treatment. Ultimately, widespread clinical adoption will depend on prospective trials comparing FLASH particle therapy with established modalities, with endpoints focused on toxicity, disease control, and patient-reported quality of life.

  PublisherDOI

• Radiobiological and Clinical Advantages of Proton Therapy in Modern Cancer Treatment

  Cancers · 2026-03-09

  articleOpen access

  BACKGROUND/OBJECTIVES: Proton therapy has emerged as an advanced radiotherapy modality due to its unique physical dose distribution and its distinct radiobiological properties. The finite range of protons in tissue enables highly conformal dose delivery with minimal exit dose, significantly reducing irradiation of surrounding normal tissues compared to photon-based radiotherapy. Beyond these physical advantages, proton beams exhibit a spatially varying linear energy transfer that increases toward the distal edge of the spread-out Bragg peak, leading to clustered and complex DNA damage that is more difficult for cancer cells to repair. METHODS: This review integrates experimental, computational, and clinical evidence to examine how proton-induced DNA damage, relative biological effectiveness, oxygen effects, and non-targeted responses contribute to tumor control and normal tissue sparing. RESULTS: Comparative analyses with photon intensity-modulated radiotherapy demonstrate consistent reductions in acute and late toxicities across multiple tumor sites, particularly in pediatric patients and in tumors located near critical organs. The review also discusses emerging technologies, including pencil beam scanning, image-guided and adaptive proton therapy, compact accelerator systems, and ultra-high dose rate FLASH proton therapy, which collectively aim to enhance treatment precision, biological effectiveness, and accessibility. CONCLUSIONS: Together, these developments support proton therapy as a rapidly evolving modality with significant potential to improve therapeutic outcomes in modern oncology.

  PublisherOA PDFDOI

• Supplementary Figure Legends from Parkin Deficiency Suppresses Antigen Presentation to Promote Tumor Immune Evasion and Immunotherapy Resistance

  2025-11-24

  articleOpen access

  <p>Supplementary Figure Legends</p>

  PublisherDOI

• Physicochemical indication of the FLASH effect from shoot-through proton pencil beam scanning parameters delivered under ultra-high dose rates

  Physics in Medicine and Biology · 2025-07-29

  articleOpen access

  Abstract Objective. Ultra-high dose rate (UHDR) proton pencil beam scanning (PBS) delivery results in irregular temporal-varying dose accumulation. It is difficult to establish a dose rate standard for the indication of proton PBS FLASH effect. In this work, we adopted a published physicochemical approach and investigated the impact of proton PBS UHDR parameters on the formation and downstream reactions of reactive oxygen species (ROS). Approach. From the ROS physicochemical model, the dose-rate dependent alkyl hydroperoxide (ROOH) formation was validated against published lipid peroxide absorbance data and correlated with mice skin damage data. For proton PBS delivery with specified beam current, voxelized temporal dose and ROS accumulation was calculated at the plateau region to simulate a shoot-through FLASH delivery. The ROS were obtained mimicking the irradiation of hypoxic skin. We examine the ROS-volume histogram in relation to the proton PBS delivery parameters. Main results. ROOH production clearly indicates sparing effects under UHDR. For PBS deliveries of 10 Gy to a 100 × 100 mm 2 field at 8 mm depth, the ROOH yield at 500 nA FLASH beam current is equivalent to a 8.78 Gy delivery at 1nA CONV delivery. The yield of ROOH depends strongly on the dose and beam current but has minimal dependency on the field size and spot spacing. Introducing inter-beam intervals of two minutes reduces the FLASH reduction in ROOH, consistent with reduced FLASH effect in murine experiment. Significance. The volumetric statistics of the ROOH yield showed consistent indication of FLASH effects in preclinical observations and correlated with the lipid peroxidation damage in tissue. Using simulated ROOH production metrics can potentially indicate the FLASH sparing effect under various PBS delivery parameters. Our simulations indicate that the shoot-through PBS FLASH effect depends mainly on the total dose and the pencil beam current, and is relatively independent of field sizes and spot spacings.

  PublisherDOI

• Lineage plasticity of the integrated stress response is a hallmark of cancer evolution

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-02-13 · 5 citations

  preprintOpen access

  The link between the "stress phenotype"-a well-established hallmark of cancer-and its role in tumor progression and intratumor heterogeneity remains poorly defined. The integrated stress response (ISR) is a key adaptive pathway that enables tumor survival under oncogenic stress. While ISR has been implicated in promoting tumor growth, its precise role in driving tumor evolution and heterogeneity has not been elucidated. In this study, using a genetically engineered mouse models, we demonstrate that ISR activation-indicated by elevated levels of phosphorylated eIF2 (p-eIF2) and ATF4-is essential for the emergence of dedifferentiated, therapy-resistant cell states. ISR, through the coordinated actions of ATF4 and MYC, facilitates the development of tumor cell populations characterized by high plasticity, stemness, and an epithelial-mesenchymal transition (EMT)-prone phenotype. This process is driven by ISR-mediated expression of genes that maintain mitochondrial integrity and function, critical for sustaining tumor progression. Importantly, genetic, or pharmacological inhibition of the p-eIF2-ATF4 signaling axis leads to mitochondrial dysfunction and significantly impairs tumor growth in mouse models of lung adenocarcinoma (LUAD). Moreover, ISR-driven dedifferentiation is associated with poor prognosis and therapy resistance in advanced human LUAD, underscoring ISR inhibition as a promising therapeutic strategy to disrupt tumor evolution and counteract disease progression.

  PublisherOA PDFDOI

• “Immune System Modulation with Oral Vancomycin in combination with Stereotactic Body Radiotherapy (SBRT) for medically inoperable Early-Stage Non-small Cell Lung Cancer”

  medRxiv · 2025-01-10

  preprintOpen access

  Abstract We present the results of a randomized, open-label pilot study investigating the combination of oral vancomycin and stereotactic body radiotherapy (SBRT) in early-stage non-small cell lung cancer (NSCLC). Our findings highlight vancomycin’s safety, evidenced by the absence of Grade 3 or 4 adverse events, and its potential to enhance the antitumor efficacy of SBRT. The observed enhancement is linked to vancomycin’s modulation of the gut microbiota, which triggers significant metabolic changes and immune activation, thereby contributing to improved progression-free survival (PFS) and overall survival (OS). Patients received vancomycin (125 mg, four times daily for five weeks, starting one week prior to SBRT), which induced restructuring of the gut microbiome and significant changes in the gut metabolome. Key changes included reductions in short-chain fatty acids (SCFAs) and shifts in other immunomodulatory metabolites. These metabolic shifts were associated with the activation of dendritic cells and T cells, creating a pro-inflammatory environment conducive to strengthening SBRT’s antitumor efficacy. The combination of vancomycin and SBRT presents a novel, low-toxicity therapeutic approach for early-stage NSCLC, showing promising initial outcomes. While the results are encouraging, further research with larger cohorts is necessary to verify these findings and elucidate the underlying mechanisms that contribute to the observed clinical benefits. WHAT IS ALREADY KNOWN ON THIS TOPIC Radiation therapy is a primary treatment for early-stage non-small cell lung cancer and offers excellent local control in early-stage NSCLC, the challenges of regional and distant failures which occur in up to 50% of patients, lead to increased morbidity and mortality. The gut microbiome is increasingly recognized in cancer immunotherapy. RT can induce Immunogenic Cell Death, activating the immune system and promoting abscopal effect to impact untreated lesions. Our previous preclinical studies have shown that antibiotics like vancomycin can modulate these immune effects and enhance RT’s antitumor activity. WHAT THIS STUDY ADDS This clinical study corroborates our previous preclinical findings by demonstrating the safety of vancomycin and its potential to enhance the antitumor effects of RT, despite the small cohort size. These findings suggest that vancomycin could be strategically used to improve RT outcomes. HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY Our findings prompt further investigation into this combined treatment in a larger patient cohort to confirm enhanced progression-free survival and overall survival. Exploring the impact on distal recurrences and applying this strategy to more advanced patient stages could significantly influence future research directions and clinical practices. This approach may also guide policy towards integrating microbiome modulation strategies in standard cancer treatment protocols.

  PublisherOA PDFDOI

• FLASH proton reirradiation, with or without hypofractionation, reduces chronic toxicity in the normal murine intestine, skin, and bone

  Radiotherapy and Oncology · 2025-01-27 · 22 citations

  articleOpen access

  BACKGROUND AND PURPOSE: The normal tissue sparing afforded by FLASH radiotherapy is being intensely investigated for potential clinical translation. Here, we studied the effects of FLASH proton radiotherapy (F-PRT) in the reirradiation setting, with or without hypofractionation. Chronic toxicities in three murine models of normal tissue toxicity including the intestine, skin, and bone were investigated. MATERIALS AND METHODS: In studies of the intestine, single-dose irradiation was performed with 12 Gy of standard proton RT (S-PRT), followed by a second dose of 12 Gy of F-PRT or S-PRT. Additionally, a hypofractionation scheme was applied in the reirradiation setting (3 x 6.4 Gy of F-PRT or S-PRT, given every 48 hrs). In studies of skin/bone of the murine leg, 15 Gy of S-PRT was followed by hypofractionated reirradiation with F-PRT or S-PRT (3 x 11 Gy). RESULTS: Compared to reirradiation with S-PRT, F-PRT induced less intestinal fibrosis and collagen deposition that was accompanied by significantly increased survival rate, demonstrating its protective effects on intestinal tissues in the reirradiation setting. In previously irradiated leg tissues, reirradiation with hypofractionated F-PRT created transient dermatitis that fully resolved in contrast to reirradiation with hypofractionated S-PRT. Lymphedema was also alleviated after a second course of radiation with F-PRT, along with significant reductions in the accumulation of fibrous connective tissue in the skin, compared to mice reirradiated with S-PRT. The delivery of a second course of fractionated S-PRT induced tibial fractures in 83.3% of the mice, whereas only 20% of mice reirradiated with F-PRT presented with fractures. CONCLUSION: These studies provide the first evidence of the sparing effects of F-PRT in the setting of hypofractionated reirradiation. The results support FLASH as highly relevant to the reirradiation regimen where it exhibits significant potential to minimize chronic complications for patients undergoing RT.

  PublisherOA PDFDOI

Recent grants

• (PQ10) The impact of the gut microbiome on the anti-tumor effects of radiotherapy

  NIH · $1.9M · 2018–2024

• Radiation and checkpoint blockade for cancer immune therapy

  NIH · $18.3M · 2017–2024

• NIH Grant R01CA104922

  NIH · $1.0M · 2010

• NIH Grant R01CA139362

  NIH · $1.3M · 2013

• Summer Undergraduate Program to Educate Radiation Scientists (SUPERS)

  NIH · $4.1M · 2010–2031

Frequent coauthors

• Amit Maity

  149 shared

• Ioannis I. Verginadis

  134 shared

• Artemis G. Hatzigeorgiou

  91 shared

• Nektaria Maria Leli

  69 shared

• Giorgos Skoufos

  Pasteur Hellenic Institute

  69 shared

• Ilias V. Karagounis

  University of Utah

  68 shared

• J. Alan Diehl

  68 shared

• Anastasia Velalopoulou

  University of Pennsylvania

  67 shared

Education

• PhD Biochemistry, Biochemistry and Biophysics Sciences

  University of Houston

  1994

• BS Pharmacy with Honors

  Aristotle University of Thessaloniki

  1989