Document text
Principal Investigator: STEVEN Terry ROSEN
Organization: BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
Fiscal Year: 2022
Award: $250,000
Funding agency: National Cancer Institute
Project Summary/Abstract
Novel targeted therapies for HPV-associated Non-AIDS-defining cancers (Biospecimens/Biocohort)
The incidents of non-AIDS-defining cancers (NADC) are increasing in HIV-infected individuals (HIVIIs), urging
the development of therapeutic interventions. Many HIV-associated cancers are a result of co-infections with
oncogenic viruses, and the high-risk human papillomavirus (HPV) is prevalent in the development of several
NADCs, including head-and-neck (HNC) and anal cancers. Importantly, the HPV viral oncogenes are involved
in the transformation and maintenance of these cancers and are considered unique targets in HPV-associated
malignancies. Often considered `undruggable', these viral genes are susceptible to targeted gene therapeutic
strategies and we have developed a novel, potent zinc finger protein (ZFP) that can strongly repress viral
oncogenes to elicit anti-cancer effects; a promising approach to HPV-associated NADCs. Furthermore, lipid
nanoparticles (LNPs) are a therapeutically relevant non-viral delivery system, which we have used previously for
in vivo delivery of RNA-based therapeutics. Importantly, even though the HPV oncogenes represent viable
therapeutic targets, there are no studies investigating the potential anti-proliferative effect of targeting the viral
oncogenes in HPV-associated tumors from HIVIIs in vivo. Our long-term goal is to develop innovative
interventions for the treatment of virally driven cancers emerging in HIVIIs, with the objective of this project to
use LNP-delivered ZFP repressors to inactive HPV oncogenes in NADCs. Guided by our strong preliminary data
and expertise using targeted repressors and nanoparticle delivery systems, we propose two complementary but
distinct objectives, 1) the characterization of novel, potent ZFP repressors for anti-proliferative effects in HPV-
associated cell line models relevant to NADCs, and 2) to assess LNP-delivered anti-HPV effectors to inhibit
HPV-associated HNCs from HIVIIs in a patient-derived xenograft (PDX) murine model. Collectively, this work
will be impactful by developing an innovative targeted repressor to inhibit HPV-associated NADCs, offering a
novel intervention to malignancies increasing in HIVIIs.
Terms: <2019-nCoV vaccine><AIDS Virus><AIDS associated cancer><AIDS related cancer><AIDS-Related Malignancy><AIDS-Related Malignant Neoplasm><AIDS-associated malignancies><Acquired Immune Deficiency Syndrome Virus><Acquired Immunodeficiency Syndrome Virus><Anal Cancer><Anal Cancers><Anus Cancer><Blood><Blood Reticuloendothelial System><COVID-19 vaccine><COVID19 vaccine><Cancer Genes><Cancer-Promoting Gene><Cancers><Causality><Cell Death><Cell Line><CellLine><Cervical Cancer><Cervix Cancer><Data><Dependence><Development><Engineering><Etiology><Gene Delivery><Gene-Modified><Generalized Growth><Genome><Genomics><Goals><Grant><Growth><HIV><HIV-Associated Cancer><HIV-associated malignancy><HIV-related malignancy><HIV/AIDS-associated malignancy><HIV/AIDS-related cancer><HPV><HPV 16><HPV oncogene><HPV-16><HPV-High Risk><HPV-Related Malignancy><HPV-associated cancer><HPV-associated malignancy><HPV-related cancer><HPV16><Head Cancer><Head and Neck><Head and Neck Cancer><Head and neck structure><High Risk Oncogenic HPV><High risk HPV><High risk Human Papillomavirus><High risk Human papilloma virus><Human Immunodeficiency Viruses><Human Papilloma Virus><Human Papilloma Virus-Related Malignancy><Human Papilloma Virus-Related Malignant Neoplasm><Human Papilloma Virus-associated cancer><Human Papilloma Virus-associated malignancy><Human Papilloma Virus-related cancer><Human Papillomavirus><Human papilloma viral oncogene><Human papilloma virus type 16><Human papillomavirus 16><Human papillomavirus type 16><Human papillomavirus-Related Malignancy><Human papillomavirus-Related Malignant Neoplasm><Individual><Infection><Infectious Human Wart Virus><Intervention><Intervention Strategies><LAV-HTLV-III><Lymphadenopathy-Associated Virus><Maintenance><Malignant Anal Neoplasm><Malignant Anal Tumor><Malignant Cervical Neoplasm><Malignant Cervical Tumor><Malignant Head and Neck Neoplasm><Malignant Neoplasm of the Cervix><Malignant Neoplasms><Malignant Tumor><Malignant Tumor of the Anus><Malignant Tumor of the Cervix><Malignant Tumor of the Cervix Uteri><Malignant Uterine Cervix Neoplasm><Malignant Uterine Cervix Tumor><Malignant neoplasm of anus><Malignant neoplasm of cervix uteri><Methods><Mission><Modeling><NIH><National Institutes of Health><Neck><Oncogenes><Oncogenic Viruses><Oncornaviruses><Oncovirinae><Oncoviruses><PDX model><Patient Representative><Patient derived xenograft><Persons><Promoter Regions><Promotor Regions><Proteins><Public Health><RNA Tumor Viruses><RNA based therapeutics><RNA delivery><Repressor Proteins><Research><SARS-CoV-2 vaccine><SARS-CoV2 vaccine><SARS-coronavirus-2 vaccine><Severe Acute Respiratory Syndrome CoV 2 vaccine><Severe acute respiratory syndrome coronavirus 2 vaccine><Strains Cell Lines><System><Testing><Therapeutic><Therapeutic Intervention><Tissue Growth><Transforming Genes><Tumor Viruses><United States National Institutes of Health><Uterine Cervix Cancer><Viral><Viral Genes><Viral Oncogene><Virus-HIV><Vulnerable Populations><Work><Zinc Finger Domain><Zinc Finger Motifs><Zinc Fingers><anal squamous cell carcinoma><anti-cancer><anticancer><carcinogenicity><causation><co-infection><coinfection><combat><corona virus disease 2019 vaccine><coronavirus disease 2019 vaccine><coronavirus disease-19 vaccine><cultured cell line><developmental><disease causation><gene modification><gene therapeutics><gene-based therapeutic><gene-based therapeutics><genes therapeutic><genes therapeutics><genetic promoter element><genetic promoter sequence><head/neck cancer><high risk><human papilloma virus 16><human papilloma virus oncogene><human papillomaviral oncogene><human papillomavirus associated malignancy><human papillomavirus oncogene><human papillomavirus-associated cancer><human papillomavirus-related cancer><in vivo><in vivo Model><innovate><innovation><innovative><intervention therapy><interventional strategy><leukemia><lipid based nanoparticle><lipid nanoparticle><malignancy><malignant head and neck tumor><mouse model><murine model><nano particle delivery><nanoparticle delivered><nanoparticle delivery><necrocytosis><neoplasm/cancer><new drug target><new druggable target><new pharmacotherapy target><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapeutic target><new therapy approaches><new therapy target><novel><novel drug target><novel druggable target><novel pharmacotherapy target><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapeutic target><novel therapy approach><novel therapy target><oncogene addiction><ontogeny><patient derived xenograft model><promoter sequence><repressor complex><success><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><therapeutic RNA><therapeutic agent development><therapeutic development><therapeutic gene><therapeutic target><tumor><type 16 Human papilloma virus><type 16 Human papillomavirus><vaccine against 2019-nCov><vaccine against SARS-CoV-2><vaccine against SARS-CoV2><vaccine against SARS-coronavirus-2><vaccine against Severe Acute Respiratory Syndrome CoV 2><vaccine against Severe acute respiratory syndrome coronavirus 2><vaccine for novel coronavirus><vulnerable group><vulnerable people><wart virus>