News
Release date:2020/9/16 5:02:37
​The goal of precision oncology is to identify patient groups with a common biological basis, select the drugs or treatment methods that are most likely to benefit the patients, and improve the effectiveness of diagnosis and treatment. At present, the scope of precision oncology is rapidly expanding. Although only a few patients can benefit from genome-matched targeted therapy, with the rapid development of this field, more and more people will benefit from it. 

Isoform and Mutant Selective Inhibitor

Isoform and mutant selective treatments can improve the efficacy and tolerability of drugs when used for precision treatment of tumors (Figure 1). For example, the PI3K pathway is one of the most common mutations in cancer, but the early use of pan-PI3K inhibitors for targeted therapy has limited effects. Compared with pan PI3K inhibitors and PI3K/mTOR dual inhibitors, the efficacy of isoform-selective PI3K inhibitors has been improved. In addition, isoform-specific inhibitors can also minimize the toxicity of the drug.

In recent years, drug selectivity has surpassed isoform selectivity and has developed towards a single mutant allele. This selectivity suppresses the mutated oncoprotein while retaining the wild-type protein. KRAS is one of the most frequently mutated oncogenes in cancer, but it has always been regarded as an undrugable target, partly because of the lack of binding pockets. However, recent improvements in small molecule design have promoted the development of highly selective inhibitors. These inhibitors react with the mutant cysteine of KRASG12C to form an irreversible covalent bond and lock the protein in an inactive GDP binding state. In the absence of this mutant cysteine, the inhibitor does not react with wild-type KRAS. Early results of phase I clinical trials of KRASG12C inhibitors show that the inhibitor has the least toxicity to NSCLC patients with KRASG12C mutations.

Isoform-Selective Inhibitors

Figure 1: Isoform-Selective Inhibitors bind to an individual protein isoform within the cell​, image source: reference [1]

Antibody-Drug Conjugations (ADC)

Another way to increase the therapeutic index is to use antibody-drug conjugations (ADCs). By directly linking cytotoxic drugs with targeting antibodies, ADCs are used to expand the therapeutic window of traditional cytotoxic drugs (Figure 2). Unfortunately, in many cases, the toxicity of ADCs is greater than expected for a variety of reasons, including the expression of normal cellular targets in host tissues, the non-specific cleavage of the toxin, and other lesser-known mechanisms. Through continuous improvement, these drugs finally began to enter clinical trials. For example, the ADC drug trastuzumab-deruxtecan (DS8201) is a combination of trastuzumab and the cytotoxic topoisomerase I inhibitor deruxtecan. The drug has shown unprecedented activity in HER2-driven cancers (including breast cancer and gastric cancer where HER2 is highly expressed). Determining the best tumor-specific targets and optimizing drug safety will be the key to further development and utilization of ADCs.

ADCs
Figure 2: Antibody-drug conjugates bind to cell-surface antigens and are internalized into the cell where they release a catatoxic payload to induce cell death. image source: reference [1]

Proteolysis-Targeting Chimeras  (PROTACS)

Another new method for precise tumor treatment is based on protein degradation products, including methods such as Proteolysis-targeting chimeras (PROTACS) and "molecular glue". This type of treatment usually involves the use of bifunctional molecules to bring the target close to the ubiquitin ligase and ultimately lead to the degradation of the target (Figure 3). At present, the application of this technology in cancer treatment is still in its infancy. Many key drivers of cancer (including transcription factors) cannot be targeted by current treatments because they are not expressed on the cell surface and therefore inaccessible to antibodies, or because they lack a binding pocket to which small molecule inhibitors can attach. PROTACs may overcome these challenges, and at the same time combine the target protein and E3 ubiquitin ligase to use the cell's endogenous protein degradation mechanism to promote the degradation of the target protein. ARV-110 is the first drug of its kind to enter Phase I clinical trials, which connects E3 ubiquitin ligase and androgen receptors in patients with prostate cancer (NCT03888612). This new method of reducing cellular protein levels may turn previously un-drugable targets into effective targets.

Proteolysis-targeting chimeras (PROTACS)
Figure 3: Proteolysis-targeting chimeras (PROTACS) bind both mutant proteins and E3 ubiquitin ligase, facilitating proteasomal degradation of the target. 
image source: reference [1]

Protein Refolders

Currently, small molecule drugs for protein refolding are being developed, which restore the lost activity by reshaping the protein conformation, thereby restoring the natural function of the mutant protein (Figure 4). This strategy has been shown to be successful in the treatment of cystic fibrosis, a non-neoplastic hereditary disease characterized by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) that produces large amounts of mucus. By allowing CFTR to reach the cell surface again and act like a wild-type protein, protein refolders can reduce the clinical sequelae of cystic fibrosis. The application of protein refolders in cancer is currently being explored and represents a new method of targeting mutant tumor suppressors. The loss-of-function mutation of the tumor suppressor TP53 is the most common mutation in cancer. There is currently no approved treatment for cancers with mutations in the TP53 gene. Efforts are currently being made to develop small molecules that restore the activity of mutant TP53 through protein refolding. In addition to increasing the number of possible drug targets, this approach also provides the additional benefit of mutation specificity, thereby reducing toxicity.

Protein refolders
Figure 4: Protein refolders enable mutant proteins to regain wild-type conformation and activity. image source: reference [1]

New-Generation Clinical Research

Another frontier of precision oncology involves new clinical trial design, that is, formulating treatment plans based on the patient's tumor genome or adjusting treatment plans based on prognostic biomarkers. For a long time, clinical trials recruit patients with specific cancer types and disease stages, and provide patients with predetermined treatment plans or random plans. As the understanding of treatment responsiveness and drug resistance biomarkers continues to deepen, the strategies used to study precision treatments are also increasing. We must continue to improve the design of clinical trials in order to precisely match individual patients with appropriate treatment options.

Conclusion

Detection at the tumor molecular level has enabled the development of precise targeted therapy for tumors, benefiting countless patients. However, research at the molecular level also shows that predicting which patients will respond to treatment is complicated. In addition, due to the poor tolerance of current treatments, many targets are still unavailable or cannot be effectively targeted. In order to achieve genome-oriented precision treatment of tumors, we must learn from previous successes and failures, optimize drug design, develop new treatment methods, and optimize the matching of patients and treatments.

Biochempeg, as a leading PEG linker supplier in the USA, provides high purity PEG derivatives for researchers to help research in the ADCs and PROTACs.

Reference:
[1] Yonina R. Murciano-Goroff, BarryS. Taylor,David M. Hyman, et al. Toward a More Precise Future for Oncology. Cancer Cell, 2020, 37: 431-442.

 

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