ASCO's research targets worthy of in-depth attention in 2021

Text | Drug Crazy

The 2021 ASCO conference has concluded, and the overwhelming progress in the research and development of new drugs in the oncology field reflects the persistent fiery state of the oncology field

01 RAD51 target characteristics

The RAD51 gene, located on chromosome 15, contains 9 exons and 8 introns, and encodes a polypeptide composed of 339 amino acids; it was first reported in 1993 and was cloned by Ogawa H et al.

When DSBs occur, the broken end is under the action of MRE11 in the MRE11/RAD50/NBS1 (MRN) ternary complex, cutting along the 5'to 3'direction, exposing the 3 bound to the replication protein A (RPA) molecule.

Figure 1.

In the above picture, you must have found the classic target BRCA.

Figure 1.

02 Varieties of drugs under development

At present, for the target of RAD51, the fastest-growing species is the inhibitor CYT-0851 developed by Cyteir.

In addition to the above-mentioned CYT-0851 and CYT-1853, most of the discoveries of RAD51 inhibitors are obtained through high-throughput screening methods.

Figure 2.

03 ASCO's summary introduction to RAD51 in 2021

The introduction of the RAD51 target and related inhibitor CYT-0851 at the 2021 ASCO Conference is mainly distributed in two report abstracts, namely Cyteir Therapeutics' first phase I/II human clinical trial study of CYT-0851 for advanced solid tumors and hematological cancers.

NO1: Cyteir Therapeutics & CYT-0851

The summary of this report mainly introduces the results of Phase I/II clinical trials of Cyteir Therapeutics’ flagship product First-in-class RAD51 inhibitor CYT-0851: 23 patients with advanced cancer (sarcoma 8; breast cancer 4; non-Hodgkin) Lymphoma 5; Pancreatic cancer 3; Ovarian cancer 2; Mucoepidermoid carcinoma 1) were included in 6 cohorts (15 mg, 20 mg, 30 mg, and 45 mg BID; 90 mg and 130 mg QD).

Figure 3.

NO2: GINECO/GINEGEPS research

The study used multiple immunofluorescence (IF) targeting RAD51, geminin (GMN), and yH2AX to measure the ability of tumor cells to recruit nuclear RAD51 lesions in the S/G2 phase in the case of double-stranded DNA damage

Figure 3.

04 RAD51 related clinical research

In addition to the summary report on RAD51 and its high-level clinical drugs in the ASCO conference, in fact, there has been a certain accumulation and understanding of the research on the target of RAD51 around the world

For breast cancer, studies have compared 23 pairs of gene expression profiles of human breast cancer primary tumors and brain metastases, and found that genes related to DNA damage repair are highly expressed in brain metastases, including BARD1 and RAD51

For further triple-negative breast cancer, studies have found that PTEN can promote DNA repair and RAD51 expression.
If both RAD51 inhibitors and PARP inhibitors are applied to PTEN-deficient triple-negative breast cancer cells, it is found that RAD51 is down-regulated and the cells inhibit PARP.
Agent sensitization
.

Studies have also confirmed that reducing the expression of RAD51 can increase the sensitivity of tumor cells to chemotherapeutic drugs and improve the therapeutic effects of cisplatin, olaparib, astaxanthin and GEM
.

05 Opportunities and Challenges

In summary, for the RAD51 target, the biggest opportunity for domestic R&D companies is that the target has a small variety of layouts, and has a large display space and inherent potential; of course, the risk factor has naturally increased a lot
.
However, as one of the targets of synthetic lethality, it has been a popular research and development direction in recent years, and there are many companies at home and abroad focusing on the research and development of this direction.
In general, it is worth investing some energy on this line.
; After all, the concept of synthetic lethality has been verified, and the marketed varieties are also in the market; therefore, the target of RAD51 is still worth trying
.

references:

1.
Felix Blanc-Durand et.
Al EFFORT: Evaluation of a RAD51 functional assay in advanced ovarian cancer, a GINECO/GINEGEPS study.
2021 ASCO, abs 5513.

2.
https://meetinglibrary.
asco.
org/record/201556/abstract

3.
https://meetinglibrary.
asco.
org/record/196842/abstract

4.
https://cyteir.
com/cyteir-pipeline

5.
Part of CNKI information