Targeting non-canonical p16 signaling to improve radiation response and outcome in head and neck cancer
靶向非经典 p16 信号传导以改善头颈癌的放射反应和结果
基本信息
- 批准号:10733627
- 负责人:
- 金额:$ 59.84万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-06-15 至 2028-05-31
- 项目状态:未结题
- 来源:
- 关键词:Automobile DrivingBRCA1 geneBiological MarkersBypassCancer BiologyCancer ControlCancer ModelCell CycleCell Cycle ArrestCellsCessation of lifeChIP-seqCisplatinClinicalClinical stratificationCoupledCyclin-Dependent Kinase Inhibitor 2ADNA DamageDNA RepairDataDiagnosisDiseaseDown-RegulationExhibitsHPV-negative head and neck cancerHead and Neck CancerHead and Neck Squamous Cell CarcinomaHuman PapillomavirusImmuneImmunocompetentImmunohistochemistryImmunologic Deficiency SyndromesIn VitroIncidenceLeftLinkMass Spectrum AnalysisMediatingMental DepressionMessenger RNAMethodologyModelingMusNatureNonhomologous DNA End JoiningOropharyngealOropharyngeal NeoplasmsOutcomePARP inhibitionPathway interactionsPatient-Focused OutcomesPatientsPersonsPharmaceutical PreparationsPoly(ADP-ribose) Polymerase InhibitorPre-Clinical ModelProteinsQuality of lifeRadiationRadiation ToxicityRadiation therapyRecurrenceRepressionResistanceSalivarySignal PathwaySignal TransductionSp1 Transcription FactorSuicideSurvivorsTestingToxic effectUp-RegulationWorkarmbrca genecancer cellclinical developmentcohortgenetic signaturehead and neck cancer patienthomologous recombinationimprovedin vitro Assayinhibitormouse modelnovelnovel therapeuticsoral HPV-positive head and neck cancersoverexpressionprecision medicineprecision oncologyradiation responseresponsestandard of caretherapy resistanttranscriptome sequencingtreatment responsetumorubiquitin-protein ligaseubiquitin-specific protease
项目摘要
PROJECT SUMMARY
Head and neck cancer (HNC) is devastating. Even in the setting of curable disease, 1 of every 2 patients
diagnosed ultimately succumb. Additionally, survivors are left with debilitating toxicity due in large part to the
toxicity of radiation, leading to poor quality of life increased rates of depression and suicide. Therefore, there is
a critical need to develop precision oncology approaches which match radiation treatment approaches to HNC
biology.
HPV-associated (HPV+) HNC most commonly arises in the oropharynx (OPC) and is associated with much
greater sensitivity to radiation. However, up to 20% of patients with HPV+ tumors will also be failed by
radiation. Conversely, HPV- HNC that express p16 exhibit favorable outcomes compared to truly p16 negative
tumors. This proposal seeks to understand why this is so. Specifically, we have identified the protein p16, a
clinical surrogate for HPV, to be driving response to radiation and PARP inhibition outside of its usual cell cycle
regulatory function, by inhibiting DNA damage repair (DDR).
Although p16 is generally thought to be functionally inactive in HPV+ HNC, and absent in HPV- HNC, our data
suggests that p16 is functioning via non-canonical signaling in HNC to induce a state of BRCAness and is key
to understanding the differential radiation response in HPV+ and HPV- tumors. In this proposal we build upon
the substantial data we have generated for a non-canonical p16-mediated pathway active in HNC – leading to
upregulation of HUWE1, downregulation of USP7 and a shift in DDR – by first characterizing the relationship
between p16 and Sp1. Although, we have linked Sp1 to the activation of our non-canonical p16 signaling
pathway, as well as outcome in HNC following the combination of cisplatin and radiation, the nature of this
interaction is unclear. We will both characterize this interaction as well as utilize state-of-the-art methodology to
globally characterize the effects of p16 and Sp1 on mRNA and protein levels within HNC pre-clinical models
and patient tumors. We will then comprehensively examine the relationship between p16 and Sp1 on DDR and
radiation or Olaparib response using a combination of immunodeficient and -competent murine orthotopic
models as well as 400 HPV+ and HPV- OPC tumors treated uniformly with cisplatin and radiation in the largest
cohort of its kind to date. Finally, we will utilize USP7 inhibitors in clinical development in combination with
either radiation or PARP inhibition in pre-clinical models.
Completion of this project will establish biomarkers of outcome in both HPV+ and HPV- HNSCC downstream
of p16, evaluate USP7 as a viable target for sensitization to radiation and Olaparib, and identify novel targets
for precision medicine in HNC.
项目总结
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Heath Devin Skinner其他文献
Cancer care and outreach in the South Asian Association for Regional Cooperation (SAARC) region: overcoming barriers and addressing challenges
南亚区域合作联盟(南盟)地区的癌症护理和外展:克服障碍和应对挑战
- DOI:
10.1016/s1470-2045(24)00514-x - 发表时间:
2024-12-01 - 期刊:
- 影响因子:35.900
- 作者:
M Saiful Huq;Sandhya C Acharya;Saugat Poudyal;Susmita Sharma;Sudhir R Silwal;Simit Sapkota;Manish Gautam;Mohammad M Haque;A F M Kamal Uddin;Sanjeeva Gunasekara;K Govind Babu;Ugyen Tshomo;Ahmad J Safi;Ahmed I Masood;Mostafa A Sumon;Shaila Purvin;Mohammad A Hai;Heath Devin Skinner;Stephen Avery;Wilfred Ngwa;Krishni Wijesooriya - 通讯作者:
Krishni Wijesooriya
Cancer care and outreach in South Asian Association for Regional Cooperation (SAARC) countries: from epidemiology and the National Cancer Control Programme to screening, diagnosis, and treatment
南亚区域合作联盟(南盟)国家的癌症护理与外展:从流行病学和国家癌症控制规划到筛查、诊断和治疗
- DOI:
10.1016/s1470-2045(24)00521-7 - 发表时间:
2024-12-01 - 期刊:
- 影响因子:35.900
- 作者:
M Saiful Huq;Sandhya C Acharya;Susmita Sharma;Saugat Poudyal;Simit Sapkota;Sunil Shrestha;Manish Gautam;Sudhir R Silwal;Mohammad M Haque;A F M Kamal Uddin;Sanjeeva Gunasekara;K Govind Babu;Ugyen Tshomo;Ahmad J Safi;Ahmed I Masood;Mostafa A Sumon;Mohammad A Hai;Altaf Hossain;Shaila Purvin;Heath Devin Skinner;Krishni Wijesooriya - 通讯作者:
Krishni Wijesooriya
Heath Devin Skinner的其他文献
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{{ truncateString('Heath Devin Skinner', 18)}}的其他基金
Project 2: Optimizing patient selection and deintensified therapy for human papillomavirus positive (HPV+) oropharyngeal cancer (OPC)
项目 2:优化人乳头瘤病毒阳性 (HPV) 口咽癌 (OPC) 的患者选择和去强化治疗
- 批准号:
10704509 - 财政年份:2004
- 资助金额:
$ 59.84万 - 项目类别:
Project 2: Optimizing patient selection and deintensified therapy for human papillomavirus positive (HPV+) oropharyngeal cancer (OPC)
项目 2:优化人乳头瘤病毒阳性 (HPV) 口咽癌 (OPC) 的患者选择和去强化治疗
- 批准号:
10331958 - 财政年份:2004
- 资助金额:
$ 59.84万 - 项目类别:
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