About

Ahmed Diab, PhD, is an Assistant Professor of Otorhinolaryngology: Head and Neck Surgery at the Perelman School of Medicine at the University of Pennsylvania. His research expertise encompasses cancer immunology and immunotherapy, tumor microenvironment, and virology. Dr. Diab is a core member of the Center for Genome Integrity and holds memberships in the Institute of Translational Medicine and Therapeutics, the Institute for Immunology & Immune Health (I3H), and the Abramson Cancer Center Cancer Therapeutics Program. His work involves understanding the immune response in cancer, particularly head and neck squamous cell carcinoma, and exploring therapeutic strategies such as WEE1 inhibition and immune control of HPV+ tumors. Dr. Diab has contributed to advancing knowledge in tumor-intrinsic and immune-related features associated with treatment failure in HPV-related cancers and has investigated the effects of viral oncoproteins on clinical behavior in HPV-related oropharyngeal cancers.

Research topics

• Genetics
• Biology
• Cancer research
• Cell biology

Selected publications

• Tumor-intrinsic and immune-related features associated with treatment failure in human papillomavirus-related oropharyngeal cancer

  JNCI Journal of the National Cancer Institute · 2025-03-11 · 2 citations

  articleOpen access

  BACKGROUND: Limited understanding of the biology predisposing certain human papillomavirus-related (HPV+) oropharyngeal squamous cell carcinomas (OPSCCs) to relapse impedes therapeutic personalization. We aimed to identify molecular traits that distinguish recurrence-prone tumors. METHODS: Fifty HPV+ OPSCCs that later recurred (cases) and 50 nonrecurrent controls matched for stage, therapy, and smoking history were RNA-sequenced. Groups were compared by gene set enrichment analysis, and select differences were validated by immunohistochemistry. Features discriminating groups were scored in each tumor using gene set variation analysis, and scores were evaluated for recurrence prediction ability. RESULTS: Cases downregulated pathways linked to antitumor immunity (FDR-adjusted P < .05) and contained fewer tumor-infiltrating lymphocytes (P < .001), including cytotoxic T-cells (P = .005). Cases also upregulated pathways related to cell division and other aspects of tumor progression. Upregulated and downregulated pathways were respectively used to define a tumor progression score (TPS) and immune suppression score (ISS) for each tumor. Correlation between TPS and ISS (r = .603, P < .001) was potentially explained by observed upregulation of DNA repair pathways in cases, which might enhance their progression directly and by limiting cytosolic DNA-induced inflammation. Accordingly, cases contained fewer double-strand breaks based on staining for phospho-RPA32 (P = .006) and γ-H2AX (P = .005) and downregulated the cytosolic DNA sensing pathway. A combined score derived from TPS and ISS optimized recurrence prediction and stratified survival in a manner generalizable to 3 external cohorts. CONCLUSIONS: We describe a potential link in HPV+ OPSCCs between reduced DNA damage and other tumor-intrinsic and immune-related contributors to recurrence risk, opening opportunities to detect and target this high-risk biology.

  PublisherOA PDFDOI

• E2 displacement of CIP2A from TOPBP1 activates the DNA damage response during papillomavirus life cycles

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-10-15 · 3 citations

  preprintOpen access

  The papillomavirus life cycle is intricately linked to epithelial differentiation, and the virus manipulates the differentiation process to facilitate viral production. One such manipulation is activation of the DNA damage response (DDR) which promotes viral replication via homologous recombination. This report demonstrates that the papillomavirus transcription/replication/segregation factor E2 activates the DNA damage response (DDR). During differentiation, E2 displacement of CIP2A from TOPBP1 causes CIP2A to bind and inhibit PP2A resulting in DDR activation via ATM phosphorylation. The DDR promotes inhibitory interaction of DBC1 with the class III deacetylase SIRT1, which further boosts the DDR via increased acetylation and stability of viral and host proteins. E2 forms a complex with TOPBP1 and ATM, while preventing ATR activation by blocking TOPBP1-ATR interaction. This "ATM up ATR down" phenotype promotes viral replication via ATM promotion of homologous recombination, and cell proliferation via inhibition of ATR. We demonstrate this mechanism of DDR activation in multiple systems: keratinocytes expressing only E2, in foreskin keratinocytes immortalized by HPV16, in HPV16 positive keratinocytes derived from a cervical lesion, in pre-neoplastic lesions induced by mouse papillomavirus MmuPV1, in head and neck cancer cell lines that retain E2 expression, and in HPV16 positive oropharyngeal patient derived xenografts that retain E2 expression. ATM inhibition preferentially killed cells expressing E2, presenting a novel strategy for treating HPV early preneoplasia and a large subset of HPV+ oropharyngeal cancers retaining E2 expression and episomal genomes.

  PublisherOA PDFDOI

• 1421 WEE1 inhibition triggers tumor microenvironment-dependent antitumor immunity against HPV+ HNSCC tumors

  Regular and Young Investigator Award Abstracts · 2024-11-01

  articleOpen access1st authorCorresponding

  <h3>Background</h3> FDA approval of immune checkpoint inhibitors (ICIs) as a treatment for head and neck squamous cell carcinoma (HNSCC) confirmed the power of harnessing the immune system for HNSCC therapy. As response rates remain low, research aimed at defining new therapeutic targets that can improve ICI therapy outcomes. Among novel therapeutic strategies, AZD1775 selectively inhibits the WEE1 kinase, causing premature mitosis and tumor cell death; this drug is being tested in clinical trials for patients with a variety of cancers including HNSCC. AZD1775 was recently shown to augment the efficacy of ICIs and other immune-targeted therapies in several models of solid tumors. <h3>Methods</h3> To study the immunomodulatory potential of AZD1775 in HPV+ HNSCC, we used the syngeneic HPV+ mEER model driven by HPV16 E6, E7 and mutated Ras. We evaluated the antitumor efficacy of AZD1775 in wild-type immunocompetent C57BL/6 mice, as well as in NSG mice which lack adaptive immunity. Noting that HPV16 E7 inhibits STING function, and that innate immune signaling via the dsDNA-sensing cGAS/STING pathway is a mechanism of AZD1775-induced antitumor immunity, we also evaluated AZD1775’s antitumor efficacy in STING-deficient C57BL/6 mice. Follow-up immunophenotyping approaches including single-cell whole transcriptome sequencing (scRNAseq), flow cytometry and bulk mRNA expression analysis using the Nanostring nCounter immune profiling panel of mEER tumors from wild-type C57BL/6 treated ± AZD1775. <h3>Results</h3> Our preliminary data shows that AZD1775 monotherapy caused tumor regression and prolonged survival in the immunocompetent wild-type mEER-bearing mice but not in mice lacking innate or adaptive immunity. We also observed a selective increase in cytotoxic CD8+ T cell and NK cell accumulation in AZD1775-treated tumors and activated several immune checkpoints. Our bulk transcriptomic analysis revealed an upregulation in genes involved in interferon gamma-induced genes as well as genes involved in lymphovascular endothelial cells (LECs) in AZD1775-treated tumors. Our scRNAseq analysis revealed an expansion of the LEC compartment in the AZD1775-treated tumors suggesting a role for lymphatic vasculature remodeling in promoting immune infiltration and surveillance following WEE1 inhibition. Ongoing studies are dissecting how WEE1 inhibition modulates tumor lymph vasculature as a means to promoting antitumor immunity against HPV+ HNSCCs. <h3>Conclusions</h3> Our data suggests that WEE1 inhibition can remodel the tumor lymphatic vasculature to promote antitumor immunity against HPV+ HNSCC tumors. A mechanistic understanding of how cell cycle checkpoint inhibition and HPV infection alter the larger tumor microenvironment may help inform the development of immunomodulatory therapy regimens that maximize the antitumor efficacy of WEE1 inhibition. <h3>Acknowledgements</h3> This research was supported by a Technology Pilot Award from the Fred Hutch Pathogen Associated Malignancies Integrated Research Center and a k99DE030194 from the National Institute of Dental and Craniofacial Research to Ahmed Diab.

  PublisherOA PDFDOI

• Association of oropharyngeal cancer recurrence with tumor-intrinsic and immune-mediated sequelae of reduced genomic instability

  bioRxiv (Cold Spring Harbor Laboratory) · 2024-11-04

  preprintOpen access

  Background: Limited understanding of the biology predisposing certain human papillomavirus-related (HPV+) oropharyngeal squamous cell carcinomas (OPSCCs) to relapse impedes therapeutic personalization. We aimed to identify molecular traits that distinguish recurrence-prone tumors. Methods: 50 HPV+ OPSCCs that later recurred (cases) and 50 non-recurrent controls matched for stage, therapy, and smoking history were RNA-sequenced. Groups were compared by gene set enrichment analysis, and select differences were validated by immunohistochemistry. Features discriminating groups were scored in each tumor using gene set variation analysis, and scores were evaluated for recurrence prediction ability. Results: Cases downregulated pathways linked to anti-tumor immunity (FDR-adjusted p<.05) and contained fewer tumor-infiltrating lymphocytes (p<.001), including cytotoxic T-cells (p=.005). Cases also upregulated pathways related to cell division and other aspects of tumor progression. Upregulated and downregulated pathways were respectively used to define a tumor progression score (TPS) and immune suppression score (ISS) for each tumor. Correlation between TPS and ISS (r=.603, p<.001) was potentially explained by observed upregulation of DNA repair pathways in cases, which might enhance their progression directly and by limiting cytosolic DNA-induced inflammation. Accordingly, cases contained fewer double-strand breaks based on staining for phospho-RPA32 (p=.006) and γ-H2AX (p=.005) and downregulated pro-inflammatory components of the cytoplasmic DNA sensing pathway. A combined score derived from TPS and ISS optimized recurrence prediction and stratified survival in a manner generalizable to three external cohorts. Conclusions: We provide novel evidence that limiting genomic instability makes tumor-intrinsic and immune-mediated contributions to HPV+ OPSCC recurrence risk, opening opportunities to detect and target this treatment-resistant biology.

  PublisherOA PDFDOI

• The imprint of viral oncoproteins on the variable clinical behavior among human papilloma virus-related oropharyngeal squamous cell carcinomas

  Tumour Virus Research · 2024-11-01

  reviewOpen accessCorresponding

  Human papilloma virus-related (HPV+) oropharyngeal squamous cell carcinomas (OPSCCs) are variable in their progression, immune landscape, treatment responses, and clinical outcomes. Their behavior is impacted not only by differences in host genomic alterations but also by diversity in levels and activity of HPV-encoded oncoproteins. Striking differences in HPV mRNA levels are found among HPV+ OPSCCs and likely derive in part from variations in the structurally diverse mix of integrated and episomal HPV genomes they often contain. Viral oncoprotein levels and function are also impacted by differential splicing of the two long polycistronic transcripts of HPV16, the HPV type within most HPV+ OPSCCs. Further variation in viral oncoprotein function arises from the distinct lineages and sub-lineages of HPV16, which encode polymorphisms in functionally important portions of oncogenes. Here we review the limited current knowledge linking HPV mRNA expression and splicing to differences in oncoprotein function that likely influence OPSCC behavior. We also summarize the evolving understanding of HPV16 physical genome state and genetic variants and their potential contributions to HPV oncoprotein levels and function. Addressing considerable remaining challenges in defining the quantitative and qualitative imprint of HPV oncoproteins on each OPSCC holds promise to guide personalization of therapy for this disease.

  PublisherDOI

• Abstract A33: WEE1 inhibition induces antitumor immune responses in HPV16 E6/E7-driven head and neck cancer

  Cancer Immunology Research · 2022-12-01

  article1st authorCorresponding

  Abstract Human papilloma virus (HPV)-related head and neck squamous cell carcinoma (HNSCC) has already surpassed cervical cancer as a the most common HPV-related cancer in the United States. While HPV+ HNSCC patients have generally good survival, they suffer from life-long chemoradiotherapy-related morbidities. Current data is insufficient to inform de-intensification of standard chemoradiotherapy or the development of targeted therapies. FDA approval of immune checkpoint inhibitors (ICIs) as HNSCC treatment confirmed the power of harnessing the immune system for HNSCC therapy. However, response rates remain low and the favorable prognosis of HPV+ patients largely precludes them from receiving ICIs as part of standard care. Research aimed at elucidating the immune profile of HPV+ HNSCC is expected to help identify patients who would likely benefit from ICI therapy and to define new therapeutic targets in this patient population. Among novel therapeutic strategies, AZD1775 selectively inhibits the WEE1 cell cycle checkpoint kinase, causing premature mitosis and tumor cell death; this drug is being tested in clinical trials for patients with a variety of cancers including HNSCC. Our phase I clinical trial previously tested the safety and efficacy of WEE1i, given early as a neoadjuvant with standard chemotherapy. Two of the three extreme responders were HPV+ patients, suggesting a unique hypersensitivity of HPV+ HNSCC to WEE1i. In the preclinical setting, we recently showed that HPV16 E6/E7 oncoproteins sensitize HNSCC cells to WEE1i monotherapy through activation of a FOXM1-CDK1 circuit that drives mitotic gene expression and DNA damage. We also showed that elevated basal FOXM1 activity predisposes HPV+ HNSCC to AZD1775-induced toxicity. Of note, WEE1 inhibition was recently shown to augment the efficacy of ICIs and other immune-targeted therapies in several models of solid tumors. However, WEE1i is largely ineffective against HPV- syngeneic HNSCC models (carcinogen-induced, p53 deficient, Ras-mutated). To test if WEE1i monotherapy induces antitumor immunity in HPV+ HNSCC tumor models, we compared the response to AZD1775 in immunocompetent and immunodeficient mice bearing a transplantable murine HPV16E6, E7 and hRas (mEER)-driven tumors. AZD1775 monotherapy caused tumor regression and prolonged survival in the immunocompetent but not in the immunodeficient mice. To investigate whether AZD1775 alters the immune tumor microenvironment (TME), we performed flow cytometric immunophenotyping of mEER tumors following WEE1 inhibition. We observed a selective increase in the prevalence of CD8+ T cells in AZD1775-treated tumors, without a clear change in all other immune cell subsets examined, suggesting that WEE1 inhibition alters the composition of the TME of HPV+ HNSCC in favor of cytotoxic CD8+ T cells. These results may explain at least in-part the unique hypersensitivity of HPV+ HNSCC to AZD1775. Understanding how WEE1 inhibition modulates the TME may inform the development of HPV-specific combination therapies that include AZD1775 and immunotherapies. Citation Format: Ahmed Diab, Jeff Kwak, Yasser Haussaini, McGarry Houghton, Bruce Clurman. WEE1 inhibition induces antitumor immune responses in HPV16 E6/E7-driven head and neck cancer [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy; 2022 Oct 21-24; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(12 Suppl):Abstract nr A33.

  PublisherDOI

• Author response: Global and context-specific transcriptional consequences of oncogenic Fbw7 mutations

  2022-02-14

  peer-reviewOpen access
  PublisherDOI

• Abdominal Ultrasonographic Findings in the Typhoid Fever in Pediatric Patients

  Benha Journal of Applied Sciences · 2021-02-01

  articleOpen access

  Typhoid fever is a fundamental irresistible illness of worldwide conveyance brought about by Salmonella Typhi. It is perhaps the most well-known bacterial reasons for intense febrile ailment in the creating scene. A complete analysis of typhoid fever is made by hemoculture just as the Widal test. USG is one of the demonstrative devices. The current examination was led to break down the handiness of USG in the determination of typhoid fever. This cross sectional examination was done on 50 pediatric patients matured 5-15 years who were clinically suspected to have typhoid fever. Blood tests of patients exposed to blood culture and Widal test and USG was acted in all patients. out of 50 patients Males were 27 cases and females were 23 cases. Out of 50 patients, 50 cases demonstrated splenomegaly on day 5 which diminished to 39 cases on day 10 and diminished to 29 cases on day 15. Hepatomegaly was available in 20 cases on day 5 at that point diminished to 7 cases on day 10 at that point got negative on day 15. Mesenteric lymphadenopathy was available in 21 cases on day 5 at that point diminished to 11 cases on day 10 at that point diminished to 6 cases on day 15. Acalculus cholecystitis was available in 15 cases on day 5 at that point diminished to 9 cases on tenth day at that point perished to 5 cases on fifteenth day. Gut thickening was in 12 cases on day 5 at that point diminished to 7 cases on day 10 at that point got negative on day 15. USG is one of the solid indicative instruments in recognition of typhoid fever in youngsters. Highlights, for example, hepatomegaly, Splenomegaly, mesentric lymphadenopathy, acalculus cholecystitis and entrail thickening ought to be considered for the analysis of typhoid fever.

  PublisherOA PDFDOI

• FOXM1 drives HPV+ HNSCC sensitivity to WEE1 inhibition

  Proceedings of the National Academy of Sciences · 2020 · 34 citations

  1st authorCorresponding
  • Cancer research
  • Biology
  • Cell biology

  Head and neck squamous cell carcinoma (HNSCC) associated with high-risk human papilloma virus (HPV) infection is a growing clinical problem. The WEE1 kinase inhibitor AZD1775 (WEE1i) overrides cell cycle checkpoints and is being studied in HNSCC regimens. We show that the HPV16 E6/E7 oncoproteins sensitize HNSCC cells to single-agent WEE1i treatment through activation of a FOXM1-CDK1 circuit that drives mitotic gene expression and DNA damage. An isogenic cell system indicated that E6 largely accounts for these phenotypes in ways that extend beyond p53 inactivation. A targeted genomic analysis implicated FOXM1 signaling downstream of E6/E7 expression and analyses of primary tumors and The Cancer Genome Atlas (TCGA) data revealed an activated FOXM1-directed promitotic transcriptional signature in HPV+ versus HPV- HNSCCs. Finally, we demonstrate the causality of FOXM1 in driving WEE1i sensitivity. These data suggest that elevated basal FOXM1 activity predisposes HPV+ HNSCC to WEE1i-induced toxicity and provide mechanistic insights into WEE1i and HPV+ HNSCC therapies.

  PublisherOA PDFDOI

• Glycometabolic Disorders in Patients with Β -Thalassemia Major in Egypt

  Benha Journal of Applied Sciences · 2020-02-01

  articleOpen access

  Beta thalassemia is one of the most common single-gene disorders that require regular blood transfusion. Repeated blood transfusions in these patients lead to the accumulation of iron in the body that result in damage to critical organs such as liver, pancreas and heart. Diabetes is one of the most common endocrine disorder worldwide that due to high prevalence and chronic nature of diabetes imposes a heavy cost on health care systemTherefore this study aimed to assess prevalence of insulin resistance in beta thalassemia major. This study included 40 B-thalassemia major patients on regular blood transfusion ,age range 6-20 years and 40 control.Detailed history was taken about units of blood transfusion and chelation therapy.clinical examination included liver and spleen size. Laboratory investigations were done in the form of serum ferritin,fasting plasma insulin ,fasting and 2hrs post prandial plasma glucose.Insulin resistance was calculated using Homeostasis Model Assessment of insulin resistance (HOMA-IR) .Our results showed that 8% of thalassemic patients had insulin resistance.There was no statistical significance between insulin resistance, units of blood transfusion and serum ferritin.conclosion:insulin resistance is common in patients of beta thalassemia major and regular follow up of blood sugar is recommended.

  PublisherOA PDFDOI

Frequent coauthors

• Fabien Zoulim

  Centre National de la Recherche Scientifique

  86 shared

• David Durantel

  Inserm

  69 shared

• Adrien Foca

  Université Claude Bernard Lyon 1

  59 shared

• Ourania Andrisani

  Purdue University Institute for Cancer Research

  42 shared

• Lia N’Guyen

  Centre de Recherche en Cancérologie de Marseille

  39 shared

• Nathalie Isorce

  Centre Léon Bérard

  39 shared

• Pascal Jalaguier

  Centre de Recherche en Cancérologie de Lyon

  39 shared

• Fouzia Amirache

  Université Claude Bernard Lyon 1

  25 shared

Labs

• Diab LabPI

Education

• B.S., Biology, Minor in Chemistry

  The American University in Cairo (AUC)

  2010

• M.S., Biosciences

  King Abdullah University of Science and Technology (KAUST)

  2011

• Ph.D., Cancer Biology

  Purdue University

  2016