Boosting cancer treatment to a golden age

While cancer immunotherapy is in full swing, other areas are developing rapidly and will play a pivotal role in the future of cancer treatment, such as antibody-drug couples, protein hydrolysis-targeted chimeras, and liquid biopsies for early detection. Globally, there are an estimated 19,500 cancer clinical trials underway and global spending on anti-cancer drugs is expected to reach $269 billion by 2025.

Immunotherapy

The primary goal of cancer immunotherapy is to activate the immune system so that it can recognize and kill tumor cells. Immunotherapy research is currently divided into five categories:

• Immune cells collected from the patient's body are changed and reintroduced into the body to boost immune activity
• Cancer cell immune escape is inhibited to boost the potential to kill cancer cells
• Oncolytic therapy involves infecting the body with customized oncolytic virus that eliminates tumors
• Monoclonal antibody
• Cancer vaccine

Trends

There are many immune checkpoint inhibitors on the market, including ipilimumab, the first FDA-approved immune checkpoint inhibitor for unresectable or advanced melanoma, and a new checkpoint inhibitor, relatlimab (Opdualag, Bristol-Myers, Squibb), recently approved by the FDA on March 18, 2022, which works by targeting LAG-3 on T cells. The FDA-approved T-cell-dependent tebentafusp-tebn (KIMMTRAK; Immunocore) is the first bispecific immunotherapy for solid tumors and the only available therapy for metastatic uveal melanoma.

Drug delivery

Antibody-drug conjugates (ADCs) are ternary complexes consisting of an antibody, a cytotoxic drug and a linker. The antibody is responsible for selectively recognizing the antigen on the surface of the cancer cell to internalize the ADC, while the cytotoxic drug is responsible for killing the cancer cell once it is released intracellularly. ADCs have been proposed for more than two decades, and problems such as low drug stability or poor targeting have led to their slow development. There are now 14 approved antibody-drug couples, ten of which were approved for marketing after 2017, and two of which have annual sales of more than $1 billion for indications such as lymphoma, breast cancer, and bladder cancer. Most recently on December 23, 2021, the FDA approved patritumab deruxtecan for the treatment of metastatic or locally advanced non-small cell lung cancer, an ADC targeting the human epidermal growth factor receptor (EGFR) HER3.

The safety of ADCs is highly dependent 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 the toxic payload and negative effects on healthy cells, but the use of a non-cleavable payload linker can reduce the occurrence of toxic side effects.

Non-druggable targets

Although genomic studies have identified approximately 600 specific protein targets associated with cancer development, as many as 400 lack pockets suitable for conventional drug binding, with some having wide, shallow pockets that repel small molecules, and others having smooth surfaces that provide few binding sites for small molecule drugs to adhere to and regulate their function. Given this situation, few drugs have been able to successfully target scaffolding proteins, transcription factors and other non-enzymatic proteins within cancer cells.

PROTACs recruit and bind target proteins and also recruit ubiquitin ligases, and this bifunctional binding triggers the degradation of the target protein, while Protac itself is recycled again for reuse. the first fully synthetic PROTAC molecule was reported in 2001, and the first PROTAC molecule with clinical application appeared in 2020, the star molecule of Arvinas, Inc. ARV-110, for the treatment of prostate cancer by targeting the androgen receptor, is currently in Phase II clinical study.

Despite their high therapeutic efficacy, PROTACs' safety is a significant concern. If a protein is required for normal cell function, using PROTACs to totally degrade it may be harmful; also, many PROTACs are not highly selective and degrade proteins other than the target protein. Nonetheless, PROTAC research is still important, as the vast majority of E3 ligases have yet to be investigated, presenting a huge opportunity to produce PROTACs that are tissue, tumor, and subcellular specific.

Early screening

While the development of new anti-cancer drugs is unquestionably crucial, early diagnosis has the same life-saving promise. Early screening, molecular typing, prognosis, and other clinical applications of cancer can be achieved by analyzing Circulating Tumor Cells (CTCs), circulating tumor DNA (ctDNA), and exosomes in cerebrospinal fluid, saliva, pleural fluid, blood, ascites, urine, and other samples. Liquid biopsy, compared to tissue biopsy, is more operable, less invasive, capable of dynamic detection, extremely sensitive, and capable of detecting tumor cells not detectable by clinical means.

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