Cancer immunotherapy is advancing rapidly, and other therapies, such as antibody-drug conjugation (ADC), proteolysis targeting chimeras (PROTAC), and liquid biopsies for early detection, are also advancing rapidly and will play an important role in future cancer treatments.
It is not difficult to find that cancer research is in a golden age, since 2015, the U.S. Food and Drug Administration (FDA) has approved more than 80 new anti-cancer drugs, accounting for about a quarter of its total new drug approvals. The number of cancer clinical trials conducted in 2020 is at an all-time high, up 60% from 2015. The focus is on indications for rare cancers. Globally, an estimated 19,500 cancer clinical trials are underway and global cancer drug spending is expected to reach $269 billion by 2025.
Cancer immunotherapy mainly activates the body's immune system so that it can recognize and kill tumor cells. At present, immunotherapy research is mainly divided into five types: cellular therapy (modifying the immune cells removed from the patient's body and importing them into the body to enhance the immune activity); immunomodulators (blocking the immune escape of cancer cells, so as to enhance the killing ability of cancer cells); oncolytic virus therapy (kills tumor cells by delivering engineered oncolytic viruses into the body); monoclonal antibodies; vaccines for cancer treatment.
Five types of cancer immunotherapy
There are many immune checkpoint inhibitors on the market, of which lpilimumab is the first immune checkpoint inhibitor approved by the FDA for the treatment of unresectable or advanced melanoma. On March 18, 2022, relatlimab (Opdualag, Bristol-Myers Squibb), a novel checkpoint inhibitor works by targeting LAG-3 on T cells. FDA-approved T-cell-dependent tebentafusp-tebn (KIMMTRAK; Immunocore), the first bispecific immunotherapy for solid tumors and the only available therapy for metastatic uveal melanoma, is exploding growing trend.
Antibody-Drug Conjugates (ADCs)
Antibody-drug conjugates (ADCs) are ternary complexes composed of antibodies, cytotoxic drugs and linkers. Antibodies are responsible for selectively recognizing cancer cell surface antigens and internalizing ADCs. Cytotoxic drugs, once released into the cell, are responsible for killing cancer cells. Antibody-drug conjugates have been proposed for more than 20 years, and their development has been slow due to problems such as low stability or poor targeting.
However, there are currently fourteen approved ADC drugs, ten of which have been approved since 2017, and two of which have annual sales of more than $1 billion for indications such as lymphoma, breast cancer and bladder cancer. On December 23, 2021, the FDA approved patritumab deruxtecan, an ADC drug targeting human epidermal growth factor receptor (EGFR) HER3, for the treatment of metastatic or locally advanced non-small cell lung cancer.
Mechanism of action of patritumab deruxtecan
The safety of ADCs largely depends on the toxic payload used, i.e., the cytotoxic drug. For some ADCs, extracellular cleavage of the ADC prior to target cell penetration may result in premature release of toxic payloads and negatively affect healthy cells, but the use of non-cleavable payload linkers can reduce the occurrence of toxic side effects.
Proteolysis targeting chimeras (PROTAC)
Although genomic studies have identified approximately 600 specific protein targets associated with cancer development, up to 400 cancer-associated proteins lack suitable pockets for conventional drug binding, some of which have wide and shallow pockets that repel small molecules. Others have smooth surfaces and few binding sites that provide adhesion sites for small molecules of drugs and regulate their function. Given this situation, few drugs can successfully target scaffold proteins, transcription factors, and other non-enzymatic proteins in cancer cells. PROTACs recruit and bind target proteins, while also recruiting ubiquitin ligases, and this bifunctional binding triggers the degradation of target proteins, while the PROTACs themselves are recycled and reused. The first fully synthetic PROTAC molecule was reported in 2001, and the first clinically used PROTAC molecule appeared in 2020. The star molecule of Arvinas, ARV-110, is currently in clinical phase II for the treatment of prostate cancer by targeting androgen receptor.
Although PROTAC has strong therapeutic efficacy, its safety remains a potential concern. Complete degradation of protein targets using PROTACs may be detrimental if the protein is critical for normal cellular function. In addition, many PROTACs are not highly selective and can degrade proteins other than the target protein. Nonetheless, PROTAC development remains of great value, and the vast majority of E3 ligases remain unexplored, presenting a huge opportunity to develop PROTACs with tissue, tumor, and subcellular selectivity.
The development history of PROTAC
The development of new cancer drugs is undoubtedly important, but early screening also has enormous life-saving power. By analyzing circulating tumor cells (CTCs), circulating tumor DNA (ctDNA) and exosomes in samples such as cerebrospinal fluid, saliva, pleural effusion, blood, ascites, urine, etc., early cancer screening, molecular classification, prognosis and other clinical applications. Compared with tissue biopsy, liquid biopsy has strong operability, less damage, dynamic detection, high sensitivity, and the ability to detect tumor cells that cannot be detected by clinical methods. It has been rated as one of the top ten emerging technologies in the world.
Liquid biopsies capture the molecular heterogeneity in metastatic cancer
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