About

Professor Roger W. Howell is a distinguished faculty member at Rutgers New Jersey Medical School, serving as a Professor of Radiology. His research primarily focuses on radiation dosimetry, radiobiology of internal radionuclides, and the biological effects of ionizing radiation. He is the Chief of the Division of Radiation Research and chairs the Rutgers Radiation Safety Committee. Dr. Howell earned his bachelor’s degree in physics in 1982 and his doctorate in 1987 from the University of Massachusetts (Amherst). He has authored over 100 scientific publications, including two books and two patents, and has contributed to various national and international committees related to radiation measurement and safety, such as the Society of Nuclear Medicine’s Medical Internal Radiation Dose Committee, NCRP, and ICRU. His work addresses critical issues in nuclear medicine, targeted radionuclide therapy, and the biological impact of low-dose radiation, with a particular interest in the bystander effects in radium-223 therapy and the development of strategies to improve cancer treatment outcomes.

Research topics

• Medicine
• Medical physics
• Biology
• Genetics
• Chemistry
• Cell biology
• Nuclear physics
• Materials science
• Cancer research
• Biochemistry
• Atomic physics
• Nanotechnology
• Surgery
• Nuclear medicine
• Physics

Selected publications

• Computational Modeling to Advance Novel Medical Isotopes for Radiotheranostics: A DOE-NIH Joint Workshop Executive Summary

  Radiation Research · 2025-05-02

  article

  The DOE-NIH Joint Workshop on Computational Modeling to Advance Novel Medical Isotopes for Radiotheranostics, held on September 27, 2024, brought together experts from government, academia, and industry to address critical challenges in radionuclide production and clinical translation. The workshop emphasized interdisciplinary collaboration, particularly between the Department of Energy (DOE) and the National Institutes of Health (NIH), to strengthen the domestic isotope supply, streamline regulatory pathways, and further integrate computational tools into radiopharmaceutical therapy (RPT). Key discussions explored the role of AI-driven modeling, machine learning, and digital twin technologies in optimizing dosimetry, dynamically personalizing treatments, and reducing time to clinical adoption. Advances in predictive computational modeling were highlighted as essential for improving radionuclide yield, purity, and synthesis efficiency. Regulatory considerations and equitable access were central themes, with participants advocating for harmonized global standards, adaptive trial designs, and expanded infrastructure for clinical implementation. DOE computational and production infrastructure was emphasized. Future priorities identified include increased investment in radionuclide production infrastructure, expanded workforce development in radiopharmaceutical sciences and computational modeling, and the creation of robust public-private partnerships. The workshop concluded that continued strategic collaboration and sustained resources will be vital for advancing next-generation radiotheranostics, ensuring safe and effective therapies accessible to all patients.

  PublisherDOI

• A novel fast strategy to calculate equieffective doses under different dose rate conditions

  Medical Physics · 2025-02-15 · 1 citations

  articleOpen access

  Abstract Background Radiopharmaceutical therapy (RPT) has gained notable attention for its potential in treating difficult cancers, with [ 177 Lu]Lu‐DOTATATE being a notable example. However, the radiobiology of RPT is less understood compared to external beam radiotherapy (EBRT), and dosimetry protocols are not standardized. Organ dose limits and tumor dose‐response correlations are often based on radiobiologically motivated equieffective doses (EQDX). On top of absorbed dose, these measures are also functions of the absorbed dose rate and radiobiological parameters that quantify tissue radiosensitivity and damage repair rate. Typically, the absorbed dose and repair rates are assumed to follow a monoexponential pattern, although describing the dose rate function often requires two or more phases to describe the data. Purpose Here we present novel expressions for calculating the equieffective dose in 2 Gy fractions (EQD2) for RPT, considering various absorbed dose rate scenarios and the rate of sublethal DNA damage repair. We aimed to establish an approach that is scalable, robust, and can be used alongside various absorbed dose integration methods. Methods By assuming a simple exponential decay for DNA damage repair and employing a biexponential function for absorbed dose rate decay, we have re‐established the solutions for EQDX in a concise analytical form. Additionally, we have devised a novel hybrid solution applicable to piecewise‐defined absorbed dose‐rate functions, leveraging both numerical and analytical methodologies. To validate these expressions, simulated measurements were utilized, and comparisons were made with a fully numerical approach. We also investigated the reliability of three methodologies—fully numerical, fully analytical, and a hybrid approach—when simplifying comprehensive dosimetry protocols. Utilizing publicly available clinical data from two patients undergoing [ 177 Lu]Lu‐DOTATATE therapy, we defined the baseline absorbed dose rate model based on the best biexponential fit to four post‐injection SPECT measurements at the organ level. We then explored variations in EQD2 values resulting from the omission of the final measurement. Results The proposed expressions were found to be accurate and scalable, providing a reliable alternative to fully numerical methods. The results of the fully numerical method converged to our solutions with increasing accuracy as the extrapolation time after injection was increased. However, we found that to achieve an accuracy in EQD2 to within 2%, the numerical method had to extrapolate for up to 890 h in some cases, at which point overflow errors are likely to occur. Our hybrid method also achieved a significant decrease in computation time compared to the fully numerical method.Using data from two patients, we found that the numerical, hybrid, and analytical approaches underestimated the baseline EQD2 to tumors by 15.6 ± 9.4 %, 5.0 ± 4.2 %, and 1.5 ± 2.9 %, respectively. Conclusions Comprehensive dosimetric studies are often preferred in RPT when increased measurement accuracy is desired. Correspondingly, it is vital for radiobiological models to maintain a level of accuracy commensurate with comprehensive studies. Our proposed methods are accurate, scalable, and suitable for radiobiologically motivated RPT dosimetry.

  PublisherOA PDFDOI

• Preirradiation of Spheroids with ²²⁵Ac-Trastuzumab Improves Penetration of ²²⁵Ac-Liposomes and MIRDcell Predictions of Responses to Drug Cocktails

  Journal of Nuclear Medicine · 2025-06-12 · 2 citations

  articleOpen accessSenior author

  This investigation examined the factors involved in predicting the responses of micrometastases to targeted ²²⁵Ac-based therapies and in optimizing these therapies through the use of cocktails of radiopharmaceuticals (RPTs). <b>Methods:</b> MIRDcell version 4 was used to model the surviving fraction (SF) of cells in multicellular spheroids that were treated with cocktails of ²²⁵Ac RPTs as previously reported by Howe et&nbsp;al. in this journal. Spheroids were treated with varying activity concentrations of [²²⁵Ac]Ac-DOTA-SCN-trastuzumab (²²⁵Ac-trastuzumab) and ²²⁵Ac-DOTA–encapsulating liposomes (²²⁵Ac-liposomes). With the total activity concentration kept constant at 13.75 kBq/mL, 5 different activity distributions among the liposomes and antibodies were evaluated: 0%, 30%, 50%, 70%, and 100% of the total activity on each carrier. Penetration of the ²²⁵Ac-trastuzumab and ²²⁵Ac-liposomes into the spheroids was obtained with fluorescent surrogates in the previous work and remeasured here to determine whether preirradiating the spheroids with ²²⁵Ac-trastuzumab affected the spatiotemporal distribution of the liposomes. These data were used to compare MIRDcell-predicted SFs with experimental spheroid outgrowths. In addition, the artificial intelligence tool in MIRDcell was used to optimize the best cocktail formulation of ²²⁵Ac-antibodies and ²²⁵Ac-liposomes to achieve SFs of less than 0.0001 while minimizing the number of total decays necessary. <b>Results:</b> The penetration profiles of spheroids with 200-µm radii show a 42% increase in the total number of decays attributed to ²²⁵Ac-liposomes between 0 and 100 µm from the centers of spheroids when first pretreated with 6.5 kBq/mL ²²⁵Ac-trastuzumab. The MIRDcell predictions based on liposome penetration data obtained after preirradiation with ²²⁵Ac-trastuzumab also provided a better match to the experimental data. Artificial intelligence optimization found that although ²²⁵Ac-liposomes alone are able to sterilize all the cancer cells in the spheroid, 44% more total decays are required than when using a cocktail of ²²⁵Ac-trastuzumab and ²²⁵Ac-liposomes. <b>Conclusion:</b> Penetration of ²²⁵Ac-liposomes was enhanced by pretreatment with ²²⁵Ac-trastuzumab, and strategies to optimize penetration into micrometastases are important for RPT therapy with carrier cocktails. RPT cocktails, as opposed to single agents, may be required to eliminate circulating tumor cells, disseminated tumor cells, and micrometastases.

  PublisherOA PDFDOI

• Phospholipid scramblases TMEM16F and Xkr8 mediate distinct features of phosphatidylserine (PS) externalization and immune suppression to promote tumor growth

  Cell Death Discovery · 2025-11-06

  articleOpen access

  The phospholipid scramblases Xkr8 and TMEM16F externalize phosphatidylserine (PS) by distinct mechanisms. Xkr8 is activated by caspase-mediated proteolytic cleavage and, in synergy with the inactivation of P4-ATPase flippases, results in the irreversible externalization of PS on apoptotic cells and an "eat-me" signal for efferocytosis. In contrast, TMEM16F is a calcium-activated scramblase that reversibly externalizes PS on viable cells via the transient increase in intracellular calcium in live cells. The tumor microenvironment (TME) is abundant with exposed PS, resulting from prolonged oncogenic and metabolic stresses and high apoptotic indexes of tumors. Such chronic PS externalization in the TME has been linked to host immune evasion from interactions of PS with inhibitory PS receptors, such as TAM and TIM family receptors. Here, in an effort to better understand the contributions of apoptotic vs live cell PS-externalization to tumorigenesis and immune evasion, we employed an EO771 orthotopic breast cancer model and genetically ablated Xkr8 and TMEM16F using CRISPR/Cas9. While neither the knockout of Xkr8 nor TMEM16F showed defects in cell intrinsic properties related to proliferation, tumor-sphere formation, and growth factor signaling, both knockouts suppressed tumorigenicity in immune-competent mice, but not in NOD/SCID or RAG-knockout immune-deficient strains. Mechanistically, Xkr8-KO tumors suppressed macrophage-mediated efferocytosis, and TMEM16F-KO suppressed ER stress/calcium-induced PS externalization. Our data support an emerging idea in immune-oncology that constitutive PS externalization, mediated by scramblase dysregulation on tumor cells, supports immune evasion in the tumor microenvironment. This links apoptosis/efferocytosis and oncogenic stress involving calcium dysregulation, contributing to PS-mediated immune escape and cancer progression.

  PublisherOA PDFDOI

• Comparison of targeting two antigens (GPA33 versus HER2) for ²²⁵Ac-pretargeted alpha-radioimmunotherapy of colorectal cancer

  Theranostics · 2025-06-20 · 3 citations

  articleOpen access

  Purpose: Curative therapies remain a significant unmet need for advanced human colorectal cancer (CRC).The aim of this study was to establish a 3-step 225 Ac-DOTA pretargeted radioimmunotherapy (PRIT) system for human CRC, targeting two individual antigens: glycoprotein A33 (GPA33) and human epidermal growth factor receptor 2 (HER2).Methods: In vitro cellular uptake and internalization assays, as well as survival assays (colony forming) were performed in GPA33-and HER2-positive SW1222 human CRC cells.In vivo biodistribution and therapy studies were performed with two human CRC xenograft mouse models.Results: For both antigens, treatment with up to 74 kBq 225 Ac-DOTA-PRIT in SW1222-tumored mice significantly enhanced overall survival in comparison to controls, including histologic cures.The uptake of 225 Ac at the tumor correlated with antigen expression (antigen expression for GPA33:HER2 is 5:1).Cellular assays showed no significant differences in internalized fraction or nucleus-associated radioactivity between the two targets.GPA33 had a higher absorbed dose to the nucleus (1.3 Gy vs. 0.65 Gy for HER2), resulting in reduced clonogenic survival.A single cycle of either GPA33 or HER2 DOTA-PRIT (37 kBq; 193.31Gy and 113.91 Gy (relative biological effectiveness [RBE] = 5), respectively) was equally effective.No chronic nephrotoxicity was seen at 20 Gy (RBE = 5).The efficacy of GPA33-directed 225 Ac-DOTA-PRIT was also confirmed in a patient-derived xenograft model. Conclusion:In summary, 225 Ac-DOTA-PRIT to GPA33 or HER2 was highly effective and safe in preclinical models of human CRC.Tumor response to treatment could not be predicted by nuclear absorbed dose alone, highlighting the importance of comprehensive micro-and macro-dosimetry.

  PublisherOA PDFDOI

• Phospholipid Scramblases TMEM16F and Xkr8 mediate distinct features of Phosphatidylserine (PS) externalization and immune suppression to promote tumor growth

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-04-18 · 1 citations

  preprintOpen access

  The phospholipid scramblases Xkr8 and TMEM16F externalize phosphatidylserine (PS) by distinct mechanisms. Xkr8, is activated by caspase-mediated proteolytic cleavage, and in synergy with inactivation of P4-ATPase flippases, results in the irreversible externalization of PS on apoptotic cells and an "eat-me" signal for efferocytosis. In contrast, TMEM16F is a calcium activated scramblase that reversibly externalizes PS on viable cells via the transient increase in intracellular calcium in live cells. The tumor microenvironment (TME) is abundant with exposed PS, resulting from prolonged oncogenic and metabolic stresses and high apoptotic indexes of tumors. Such chronic PS externalization in the TME has been linked to host immune evasion from interactions of PS with inhibitory PS receptors such as TAM and TIM receptors. Here, in an effort to better understand the contributions of apoptotic vs live cell PS-externalization to tumorigenesis and immune evasion, we employed an E0771 orthotopic breast cancer model and genetically ablated Xkr8 and TMEM16F using CRISPR/Cas9. While neither the knockout of Xkr8 nor TMEM16F showed defects in cell intrinsic properties related to proliferation, tumor-sphere formation, and growth factor signaling, both knockouts suppressed tumorigenicity in immune-competent mice, but not in NOD/SCID or RAG-KO immune-deficient strains. Mechanistically, Xkr8-KO tumors suppressed macrophage-mediated efferocytosis, and TMEM16F-KO suppressed ER stress/calcium-induced PS externalization. Our data support an emerging idea in immune-oncology that constitutive PS externalization, mediated by scramblase dysregulation on tumor cells, supports immune evasion in the tumor microenvironment. This links apoptosis/efferocytosis and oncogenic stress involving calcium dysregulation, contributing to PS-mediated immune escape and cancer progression.

  PublisherOA PDFDOI

• Tumor specific delivery and radiation-enhanced tumor penetration of mesoporous silica nanoparticles for effective radionuclide therapy of ovarian peritoneal metastasis

  UNC Libraries · 2025-12-02

  articleOpen access
  PublisherDOI

• ICRU Report 99, Glossary of Contemporary Terms and Definitions in Radiation Science and Medicine

  Journal of the ICRU · 2024-12-01 · 2 citations

  article
  PublisherDOI

• MIRD Pamphlet No. 31: MIRDcell V4—Artificial Intelligence Tools to Formulate Optimized Radiopharmaceutical Cocktails for Therapy

  Journal of Nuclear Medicine · 2024-10-24 · 10 citations

  articleOpen accessSenior author

  Radiopharmaceutical cocktails have been developed over the years to treat cancer. Cocktails of agents are attractive because 1 radiopharmaceutical is unlikely to have the desired therapeutic effect because of nonuniform uptake by the targeted cells. Therefore, multiple radiopharmaceuticals targeting different receptors on a cell is warranted. However, past implementations in&nbsp;vivo have not met with convincing results because of the absence of optimization strategies. Here we present artificial intelligence (AI) tools housed in a new version of our software platform, MIRDcell V4, that optimize a cocktail of radiopharmaceuticals by minimizing the total disintegrations needed to achieve a given surviving fraction (SF) of tumor cells. <b>Methods:</b> AI tools are developed within MIRDcell V4 using an optimizer based on the sequential least-squares programming algorithm. The algorithm determines the molar activities for each drug in the cocktail that minimize the total disintegrations required to achieve a specified SF. Tools are provided for populations of cells that do not cross-irradiate (e.g., circulating or disseminated tumor cells) and for multicellular clusters (e.g., micrometastases). The tools were tested using model data, flow cytometry data for suspensions of single cells labeled with fluorochrome-labeled antibodies, and 3-dimensional spatiotemporal kinetics in spheroids for fluorochrome-loaded liposomes. <b>Results:</b> Experimental binding distributions of 4 ²¹¹At-antibodies were considered for treating suspensions of MDA-MB-231 human breast cancer cells. A 2-drug combination reduced the number of ²¹¹At decays required by a factor of 1.6 relative to the best single antibody. In another study, 2 radiopharmaceuticals radiolabeled with ^195mPt were each distributed lognormally in a hypothetical multicellular cluster. Here, the 2-drug combination required 1.7-fold fewer decays than did either drug alone. Finally, 2 ²²⁵Ac-labeled drugs that provide different radial distributions within a spheroid require about one half of the disintegrations required by the best single agent. <b>Conclusion:</b> The MIRDcell AI tools determine optimized drug combinations and corresponding molar activities needed to achieve a given SF. This approach could be used to analyze a sample of cells obtained from cell culture, animal, or patient to predict the best combination of drugs for maximum therapeutic effect with the least total disintegrations.

  PublisherOA PDFDOI

• MPD Helped Successfully Drill a Central European Well to TD After Multiple Failures in a Formation Fraught with Wellbore Instability and Formation Pressure Uncertainties

  SPE/IADC Managed Pressure Drilling and Underbalanced Operations Conference and Exhibition · 2024-09-17

  article

  Abstract MPD successfully delivered the first well in a remote Balkan region of Central Europe after multiple failed conventional drilling attempts into a reservoir fraught with formation pressure uncertainties and significant wellbore breakout. This paper discusses the MPD planning and execution strategies for managing the formation pressure uncertainties and borehole breakout, as well as the performance of the MPD system in handling larger cuttings and cavings. MPD offers many opportunities, such as using a reduced mud weight and tracking the lower pressure boundary, coupled with the ability to respond rapidly to changing formation pressures. Challenges arise when wellbore stability pressure is uncertain, leading to breakouts at the borehole wall. This results in larger cuttings and cavings that can potentially plug the choke, causing pressure fluctuations and potentially leading to charged fractures, thereby further exacerbating the situation. These scenarios require detailed analysis, extensive planning, and rapid response. The engineering team's planned response to the formation and fracture pressure uncertainties, combined with field execution and MPD system performance, enabled Shell Upstream Albania B.V. to successfully drill the well to the planned TD and secure and isolate multiple fracture zones with liner and MPC for stimulation and testing for the first time in the region. The well was drilled and completed with minimal losses while encountering major borehole breakout and with "0″ NPT due to choke plugging. MPD also enabled the client to obtain the first set of logs for the reservoir in this region with LWD. The liner was successfully run to TD, and bottom hole pressures were managed while cementing with MPD.

  PublisherDOI

Recent grants

• MIRDcell Version 3

  NIH · $1.8M · 2020–2027

• NIH Grant R01CA198073

  NIH · $1.3M · 2021

• NIH Grant RC1AI078518

  NIH · $1.1M · 2011

• NIH Grant R29CA054891

  NIH · $492k · 1997

• NIH Grant R01CA083838

  NIH · $2.2M · 2011

Frequent coauthors

• S. James Adelstein

  University of Massachusetts Boston

  99 shared

• John L. Humm

  Memorial Sloan Kettering Cancer Center

  98 shared

• B. W. Wessels

  University Hospitals Case Medical Center

  98 shared

• Joseph A. O’Donoghue

  Memorial Sloan Kettering Cancer Center

  95 shared

• Peter K. Leichner

  95 shared

• A. J. Green

  Memorial Sloan Kettering Cancer Center

  90 shared

• Edouard I. Azzam

  Canadian Nuclear Laboratories

  59 shared

• S.-E. Strand

  56 shared

Labs

• Roger W. Howell's LabPI

  Not provided

Education

• Ph.D.

  University of Massachusetts

  1987

• B.S.

  University of Massachusetts

  1982

Awards & honors

• 2004 Loevinger-Berman Award from the Society of Nuclear Medi…
• 2009 Basic Science Faculty of the Year Award from New Jersey…