Document text
Principal Investigator: Wenquan Ou
Organization: UNIV OF MARYLAND, COLLEGE PARK
Fiscal Year: 2024
Award: $235,233
Funding agency: National Cancer Institute
Project Summary/Abstract
Breast cancer is the second leading cause of cancer-related deaths of American women. In particular, no
targeted therapy is clinically available for nearly all triple negative breast cancer (TNBC). Cancer arises as a
result of accumulating genetic alterations. Therefore, developing novel strategies to precisely target the genetic
alterations of TNBC may be valuable for combating the malignant disease. TP53 is a pivotal tumor suppressor
gene inactivated by mutation or deletion in most human cancers. Tremendous effort has been made to restore
the activity of the p53 protein encoded by TP53 for cancer treatment. Unfortunately, no p53-based therapy has
been successfully translated into the clinic, due to the complexity of p53 signaling. Therefore, identifying
vulnerabilities conferred by TP53 deletion instead of restoring the p53 activity is a novel strategy for combating
cancer. In our recent work published in Nature and Nature Nanotechnology, we revealed genomic deletion of
TP53 is often accompanied by hemizygous (i.e., partial) loss of a neighboring gene POLR2A essential for cell
survival, and virtually all 53% TNBCs with TP53 deletion harbor hemizygous POLR2A loss (TP53/POLR2Aloss).
Our preliminary data show that suppressing POLR2A expression by RNA interference with small interfering
RNA (siRNA) delivered using a low pH-activated nanobomb selectively inhibits the proliferation, survival, and
tumorigenic potential of TP53/POLR2Aloss TNBC cells. The nanobomb protects the siRNA in blood and enables
endo/lysosomal escape of the siRNA into the cytosol where the siRNA performs its POLR2A inhibition function
after cell uptake. Moreover, the nanobomb-mediated delivery of POLR2A-targeting siRNA selectively inhibits
the growth of orthotopic TP53/POLR2Aloss TNBC tumors, with no evident systemic toxicity demonstrated by the
data on animal body weight and blood proteins (for liver function) and cytokines (for immune responses).
However, a small fraction of breast cancer cells overexpressed with the variant CD44 (note: not the non-
variant or normal CD44 on normal stem cells) have been shown to be particularly resistant to clinically used
chemotherapy drugs of TNBC such as paclitaxel (PTX). Since POLR2A is indispensable for cancer cells to
survive, we hypothesize that targeted co-delivery of the POLR2A-targeting siRNA and PTX to the variant
CD44+ cancer cells can overcome the TNBC drug resistance. We will further develop the aforementioned low
pH-activated nanobomb that has no active targeting, to be capable of actively targeting both the variant CD44+
cells and tumor vasculature. Since cancer metastasis is the major cause of cancer-related death, we will test
the hypothesis using not only the aforementioned orthotopic/primary TNBC tumors but also metastatic TNBC
model. Furthermore, we will investigate the mechanisms of resistance to the POLR2A-targeted therapy using
not only 2D and xenograft but also 3D TNBC models generated using microfluidic approach developed by us.
Collectively, this project may result in a novel therapy for drug-resistant TNBC with mechanistic understanding,
which is invaluable for combating TNBC and possibly many other types of cancers harboring TP53 deletion.
Terms: <3-D><3-Dimensional><3D><3D cell culture><3D culture><American><Animals><Anti-Oncogenes><Antioncogene Protein p53><Antioncogenes><Anzatax><Asotax><Bioavailability><Biological Availability><Biological Mimetics><Biomimetics><Blood><Blood Circulation><Blood Proteins><Blood Reticuloendothelial System><Bloodstream><Body Weight><Breast Cancer><Breast Cancer Cell><Breast Cancer Model><Breast Cancer Patient><Breast Tumor Patient><Breast tumor model><Bristaxol><CD44><CD44 gene><CD62P Antigens><CRISPR approach><CRISPR based approach><CRISPR method><CRISPR methodology><CRISPR technique><CRISPR technology><CRISPR tools><CRISPR-CAS-9><CRISPR-based method><CRISPR-based technique><CRISPR-based technology><CRISPR-based tool><CRISPR/CAS approach><CRISPR/Cas method><CRISPR/Cas technology><CRISPR/Cas9><CRISPR/Cas9 technology><Cancer Cause><Cancer Etiology><Cancer Suppressor Genes><Cancer Treatment><Cancers><Cas nuclease technology><Catalytic Core><Catalytic Domain><Catalytic Region><Catalytic Site><Catalytic Subunit><Cell Body><Cell Communication and Signaling><Cell Signaling><Cell Survival><Cell Viability><Cell division><Cells><Cellular Tumor Antigen P53><Cessation of life><Chemotherapy Protocol><Chemotherapy Regimen><Chemotherapy-Oncologic Procedure><Clinic><Clinical><Clustered Regularly Interspaced Short Palindromic Repeats approach><Clustered Regularly Interspaced Short Palindromic Repeats method><Clustered Regularly Interspaced Short Palindromic Repeats methodology><Clustered Regularly Interspaced Short Palindromic Repeats technique><Clustered Regularly Interspaced Short Palindromic Repeats technology><Colorectal Cancer><Combination Chemotherapy Regimen><Complex><Cytosol><DNA Directed RNA Polymerase II Polypeptide A><DNA-Dependent RNA Polymerase II><DNA-Directed RNA Polymerase II Largest Subunit><Data><Death><Defect><Deletion of DNA Sequences><Development><Dimethylbiguanidine><Dimethylguanylguanidine><Disease><Disorder><Drug resistance><Drugs><Emerogenes><Encapsulated><Endothelial Cells><Essential Genes><Foundations><GMP-140><Gene Copy Number><Gene Delivery><Gene Dosage><Gene Transcription><Generalized Growth><Genetic Alteration><Genetic Change><Genetic Transcription><Genetic defect><Genomics><Growth><Heterograft><Heterologous Transplantation><Human><Hyaluronic Acid><Hydrophobicity><Immune response><Immunological response><In Vitro><Intracellular Communication and Signaling><LECAM-3><Laser Electromagnetic><Laser Radiation><Lasers><Ligands><Lysosomes><MDU3><Malignant><Malignant - descriptor><Malignant Breast Neoplasm><Malignant Cell><Malignant Neoplasm Therapy><Malignant Neoplasm Treatment><Malignant Neoplasms><Malignant Tumor><Malignant Tumor of the Prostate><Malignant neoplasm of prostate><Malignant prostatic tumor><Mammalian Cell><Mediating><Medication><Messenger RNA><Metastasis><Metastasize><Metastatic Lesion><Metastatic Mass><Metastatic Neoplasm><Metastatic Tumor><Metformin><Micro RNA><Micro-tubule><MicroRNAs><Microfluidics><Microtubule Stabilization><Microtubules><Modern Man><Mutation><N,N-dimethyl-imidodicarbonimidic diamide><Nanotechnology><Nature><Neoplasm Metastasis><Non-Polyadenylated RNA><Onco-Suppressor Genes><Oncogenes-Tumor Suppressors><Oncoprotein p53><P-Selectin><P53><POLR2A><POLR2A gene><Paclitaxel><Paclitaxel (Taxol)><Patients><Permeability><Pgp1><Pharmaceutical Preparations><Phosphoprotein P53><Phosphoprotein pp53><Physiologic Availability><Platelet alpha-Granule Membrane Protein><Post-Transcriptional Gene Silencing><Posttranscriptional Gene Silencing><Praxel><Probability><Progenitor Cells><Proliferating><Prostate CA><Prostate Cancer><Prostate malignancy><Prostatic Cancer><Protein TP53><Public Health><Publishing><Quimioterapia><RNA><RNA Expression><RNA Gene Products><RNA Interference><RNA Polymerase B><RNA Polymerase II><RNA Polymerase II 220 kD Subunit><RNA Silencing><RNA Stability><RNA based therapeutics><RNA based therapy><RNA delivery><RNA therapy><RNAi><RPO2><RPOL2><Recessive Oncogenes><Resistance><Ribonucleic Acid><Secondary Neoplasm><Secondary Tumor><Sequence Deletion><Sequence-Specific Posttranscriptional Gene Silencing><Short interfering RNA><Signal Transduction><Signal Transduction Systems><Signaling><Small Interfering RNA><TNBC><TP53><TP53 gene><TRP53><Taxol><Taxol A><Taxol Konzentrat><Testing><Therapeutic><Tissue Growth><Transcription><Translating><Tumor Protein p53><Tumor Protein p53 Gene><Tumor Suppressing Genes><Tumor Suppressor Genes><Tumor Suppressor Proteins><Variant><Variation><Woman><Work><Xenograft><Xenograft procedure><Xenotransplantation><anti-cancer><anti-cancer therapy><biological signal transduction><breast tumor cell><cancer cell><cancer chemotherapy><cancer drug resistance><cancer metastasis><cancer therapy><cancer type><cancer-directed therapy><cell transduction><cellular transduction><chemotherapy><cytokine><deliver short interfering RNA><deliver siRNA><deliver small interfering RNA><delivery system for siRNA><delivery system for small interfering RNA><delivery vectors for siRNA><developmental><drug relapse><drug resistant><drug/agent><experience><fucan sulfate><fucoidan><fucoidin><genome mutation><genomic deletion><host response><hsRPB1><hsRPB2><human model><hydrophilicity><immune system response><immunoresponse><improved><in vivo><liposomal delivery><liposome delivery><liver function><mRNA><malignancy><malignant breast tumor><mammary cancer model><mammary tumor model><miRNA><miRNAs><miniaturize><miniaturized><model of human><mortality><mouse model><murine model><nano bomb><nano particle><nano tech><nano technology><nano-sized particle><nano-technological><nanobomb><nanoparticle><nanosized particle><nanotech><nanotechnological><neoplasm/cancer><new approaches><new drug target><new drug treatments><new druggable target><new drugs><new pharmacological therapeutic><new pharmacotherapy target><new therapeutic target><new therapeutics><new therapy><new therapy target><next generation therapeutics><novel><novel approaches><novel drug target><novel drug treatments><novel druggable target><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel pharmacotherapy target><novel strategies><novel strategy><novel therapeutic target><novel therapeutics><novel therapy><novel therapy target><oncosuppressor gene><ontogeny><overexpress><overexpression><p53 Antigen><p53 Genes><p53 Tumor Suppressor><progenitor-like cell><protein p53><resistance mechanism><resistance to Drug><resistance to cancer drugs><resistance to therapy><resistant><resistant mechanism><resistant to Drug><resistant to cancer drugs><resistant to therapy><shRNA><short hairpin RNA><short interfering RNA delivery><siRNA><siRNA delivery><small hairpin RNA><small interfering RNA delivery><stem cells><stem-like cell><systemic toxicity><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><taxane><therapeutic RNA><therapeutic resistance><therapy resistant><three dimensional><three dimensional cell culture><transduced cells><treatment resistance><triple-negative breast cancer><triple-negative invasive breast carcinoma><tumor><tumor cell metastasis><tumor growth><tumor initiation><tumor suppressor><tumorigenic><uptake><virtual><xeno-transplant><xeno-transplantation><µfluidic>