Four Therapeutic Strategies For Cancer Treatment In Future

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Four Therapeutic Strategies For Cancer
Treatment In Future

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.

Immunotherapy

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.

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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

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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)

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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.

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The development history of PROTAC

Early screening

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.

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Liquid biopsies capture the molecular heterogeneity in metastatic cancer

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References:
[1].https://www.uchicagomedicine.org/cancer/types-treatments/immunotherapy
[2].Kirchhoff D, et al. IL3RA-Targeting Antibody-Drug Conjugate BAY-943 with a Kinesin Spindle Protein
Inhibitor Payload Shows Efficacy in Preclinical Models of Hematologic Malignancies. Cancers (Basel).
2020;12(11):3464.
[3].Békés, M., Langley, D.R. & Crews, C.M. PROTAC targeted protein degraders: the past is prologue.

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Nat Rev Drug Discov 21, 181–200 (2022).
[4].Mullard A. Targeted protein degraders crowd into the clinic. Nat Rev Drug Discov. 2021
Apr;20(4):247-250.
[5].Siravegna, G., 2017. Integrating liquid biopsies into the management of cancer. Nature Reviews
Clinical Oncology 14, 531–548.
[6].Webster, P. A golden era of cancer clinical trials. Nat Med 28, 602–605 (2022)

Related articles:
[1] ADC Drugs Global Sales of 2021 and Future Prospects
[2] Global Antibody-drug Conjugates (ADCs): Approvals & Clinical Trails Review
[3] Future Perspective of PROTAC Combined With CRISPR In Anti-ancer Area
[4] Focus On PROTAC: Summary Of Targets From 2001 To 2019