New drug combo identified for liver cancer via CRISPR-Cas9 screen

Date:
January 11, 2022
Source:
The University of Hong Kong
Summary:
A research team has successfully repurposed an approved drug
ifenprodil, a vasodilator, to be used in combination with the
FDA-approved first-line drug sorafenib for hepatocellular carcinoma
(HCC) treatment. This study leveraged on their CombiGEM-CRISPR
v2.0 screening platform1 to expedite the search among the many
possible drug combinations to inhibit druggable targets in the
genome for treating HCC.



FULL STORY ==========================================================================
A research team of LKS Faculty of Medicine, The University of Hong Kong (HKUMed) has successfully repurposed an approved drug ifenprodil, a vasodilator, to be used in combination with the FDA-approved first-line
drug sorafenib for hepatocellular carcinoma (HCC) treatment. This study leveraged on their CombiGEM-CRISPR v2.0 screening platform1 to expedite
the search among the many possible drug combinations to inhibit druggable targets in the genome for treating HCC. The findings are now published
in Cancer Research.


========================================================================== Liver cancer is the sixth most common cancer and the third leading
cause of cancer related death worldwide. Despite the promising initial
response to molecularly targeted therapies, tumours are often susceptible
to developing drug resistance. It is no exception for sorafenib, the
mainstay of treatment for HCC, and the available treatment options are
very limited. Drug combination is a strategy for expanding options for
cancer treatment to reduce the risk of drug resistance and tumour relapse
that often arises in standalone treatment.

The simplicity and precision of CRISPR-Cas9 that uses guide ribonucleic
acids (RNAs) to knockout any genes in the genome make it a great tool
to identify targets for potential drug discovery and development.

Utilising the screening platform of CombiGEM-CRISPR v2.0 to generate multiplexable gene knockouts, this study rapidly characterised the
survival of cancer cells following dual-genetic knockouts in a pool
of cells linked with DNA barcodes specifying the types of genetic
alterations they carry. Instead of using conventional drug screening
array that requires handling of numerous independent multi-wells,
this platform only requires a simple experimental setup as the number
of DNA barcodes carried by a large population of cells grown in the
same culture dish could be counted in high volume via high- throughput sequencing technologies. Through screening genes and their combinations
from which hits can be translated directly into drug combinations using existing drugs, non-conventional drugs and drug combinations could be discovered and repurposed for treating cancers.

Through a combinatorial CRISPR-Cas9 screen focusing on a set of druggable targets of which their expressions are upregulated in HCC cancer stem
cells, the HKUMed research team identified two combinations harbouring
a common target known as NMDAR1 and its paired targets are two kinases
(FLT4 and FGFR3) of which both their corresponding drug inhibitor is
the first line sorafenib.

Specifically, genetically ablation of the identified gene combinations
inhibits HCC cells' growth and self-renewal ability. Based on The Cancer
Genome Atlas database, the research team also unveiled the clinical significance of NMDAR1 in HCC, where HCC patients with low level of
NMDAR1 expression show better survival outcomes.

The team also revealed the enhanced inhibition effect of the
corresponding drug combination and their underlying molecular
mechanisms. Co-administration of ifenprodil and sorafenib remarkably
reduced the cell growth and stemness in multiple HCC cell lines, patient-derived organoids and tumour xenograft models.

Additionally, the team also showed that the upregulation of unfolded
protein response, triggering of cell-cycle arrest, and downregulation
of genes associated with WNT-signaling and stemness could account for
the enhanced effects of the drug combination.

Ifenprodil has been used as a vasodilator in countries including Japan
and France with known safety history in humans. Combined with the first
line sorafenib, the HKUMed research team has successfully demonstrated
this two-drug regimen profoundly suppressed HCC cells' growth and
self-renewal ability.

'Successful drug repurposing saves the cost and time that otherwise would
be needed for developing new therapeutic agents with uncertain efficacy
and safety profile. It also increases the chance of clinical translation
of the findings from bench to bedside as the identified drug combination
could be readily tested in future trials for treating HCC. Our work has identified a potentially useful drug combination to be further tested for
the treatment of HCC patients from approved drugs, which could possibly
save or prolong patients' life,' said Dr Stephanie Ma, Associate Professor
of the School of Biomedical Sciences, HKUMed, who co-led the study.

'The application of the CombiGEM-CRISPR v2.0 platform has broadened
our scope in search for effective combinations of actionable targets
and approved/ repurposed drugs for HCC in a rapid and simple manner,
and could be extended to other cancers and diseases,' added Dr Alan
Wong Siu-lun, Assistant Professor of the School of Biomedical Sciences,
HKUMed, who co-led the research.

========================================================================== Story Source: Materials provided by The_University_of_Hong_Kong. Note:
Content may be edited for style and length.


========================================================================== Journal Reference:
1. Feng Xu, Man Tong, Cindy S.W. Tong, Becky K.C. Chan, Hoi Yee Chu,
Tin Lok
Wong, John H.C. Fong, Maggie S.H. Cheung, Kylie Hin-Man Mak,
Lakhansing Pardeshi, Yuanhua Huang, Koon Ho Wong, Gigi C.G. Choi,
Stephanie Ma, Alan S.L. Wong. A Combinatorial CRISPR-Cas9 Screen
Identifies Ifenprodil as an Adjunct to Sorafenib for Liver
Cancer Treatment. Cancer Research, 2021; 81 (24): 6219 DOI:
10.1158/0008-5472.CAN-21-1017 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2022/01/220111100024.htm

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