Published online May 24, 2022. doi: 10.5306/wjco.v13.i5.323
Peer-review started: April 9, 2021
First decision: June 28, 2021
Revised: July 6, 2021
Accepted: April 22, 2022
Article in press: April 22, 2022
Published online: May 24, 2022
Processing time: 410 Days and 11.2 Hours
The genetic basis of human cancers was elucidated via the identification of the prototypic human tumor suppressor retinoblastoma (Rb) gene by F. Hong (previously worked on phosphate transferase system governing diauxie at the Johns Hopkins University, whose alternate interpretation inspired operon concept) at the University of California at San Diego. His determination of the Rb gene sequence helped to uncover the central role of Rb in regulating the cell cycle as a component of DNA damage checkpoint at the G1 or S phase, which is regulated by cyclin-dependent kinase (Cdk) resulting in FDA-approved Cdk4/6 inhibitors for treating advanced-stage breast cancer. His discovery of Rb’s intrinsic properties to interact with DNA as well as to form oligomers like the breast cancer type 1 susceptibility protein C-terminus (BRCT) laid the foundation for understanding Rb’s function in regulating DNA replication, transcription (ex. E2F), epigenetics (histone modification), heterochromatin, and condensation. These works culminated in his discovery of the tumor-specific lytic path ‘hyperploid progression mediated death’ targeting Rb or p53 mutant cancers.
Metastatic cancer diagnosed in late-stage remains a formidable challenge, often resulting in mortality. Combinatorial regimens consisting of multiple chemotherapeutic agents administered to treat metastatic cancer incur an unacceptably high level of morbidity.
There is a great unmet need to direct or guide the intravenously injected drugs to tumors as less than 0.5% reach tumors currently, contributing to severe side effects.
Harnessing the power of molecular biology, random peptide displaying M13 bacteriophage-based library was screened by F. Hong, who previously utilized the recombinant phages to determine the genomic sequence of avian infectious bronchitis virus’ spike protein for vaccine development at the Salk Institute, which predated the emergence of COVID-19 coronavirus. The screening was conducted at the University of Texas M. D. Anderson Cancer Center using live surgically derived human head and neck squamous cell carcinoma cells. After screening 2.5 × 1012 random peptides, a single peptide TSPLNIHNGQKL (HN-1) was isolated, which is tumor-specific, translocates across the cell membrane, and capable of penetrating solid tumors for targeted drug delivery.
Through global participation, the above properties of the HN-1 peptide have been confirmed. The international endeavor also led to the development of numerous HN-1 peptide conjugated agents for therapy (taxol, doxorubicin, protein kinase C inhibiting peptide, ribonucleotide reductase inhibiting siRNA, diphtheria toxin, polyethylene glycol linked to doxorubicin, graphene oxide nanoparticle-containing doxorubicin) as well as imaging (gamma-ray emitting isotopes for radiotherapy, near-infrared fluorescent dyes for surgical navigation) of cancer. More significantly, we now know that HN-1 peptide also targets breast and thyroid (potentially cervical, lung, uterine, colon) cancers.
While analyzing its amino acid content, an important clue was obtained that pointed to discoidin domain receptor 1 (DDR1) as the HN-1 peptide’s cognate receptor. The finding is in alignment with previously accrued experimental data globally concerning the uptake route of HN-1. The identification of Rb-regulated DDR1 as the putative receptor for HN-1 opens unexpected opportunities to block cancer progression via targeting the very protein mediating metastasis.
Through abrogating metastasis, it may preempt the recurrence of refractory metastatic cancers, which inevitably arise due to the acquiring of drug resistance.