Targeted Therapies: Advancing Precision Oncology with Biomarker-Driven Treatment Strategies

It is well established that individuals respond differently to medications, and thus a one-size-fits-all approach is inappropriate. For many years, the U.S. Food and Drug Administration (FDA) has actively promoted targeted drug therapies, with the aim of fully realizing “personalized medicine” or “precision medicine” in the future. Currently, “targeted therapy” determines the most appropriate treatment regimen based on “biomarkers,” thereby enhancing drug safety, improving clinical outcomes, and reducing adverse reactions.
Appendix: Biomarkers are indicators that can be objectively measured and used to evaluate normal biological processes, pathological processes, or responses to therapeutic interventions. They may include anatomical, histological, imaging, genetic, mRNA, protein, metabolic, and other substances.

What Are Targeted Therapies?
Targeted therapy generally refers to molecularly targeted therapies or targeted cancer therapies, which involve the use of drugs or other agents to inhibit specific molecules (i.e., molecular targets) involved in the growth, spread, and migration of cancer cells; hence, it is also referred to as “precision medicine.”

Unprecedented analytical capabilities for human genes and proteins have emerged in the fields of biology and computer science, enabling the precise selection of drugs or other specific small molecules based on biomarkers. This approach facilitates precision medicine with maximal efficacy and minimal side effects. Unlike traditional cytotoxic chemotherapy and radiation therapy, it delivers targeted therapy against molecular pathways underlying malignant phenotypes, focusing on specific tumor cell receptors or signaling processes. This not only curbs tumor migration and progression but also reduces toxicity to normal cells. In contrast, conventional chemotherapeutic agents lack selectivity, attacking all dividing cells indiscriminately.

Therefore, targeted therapy has become the focal point of current anticancer drug development and serves as the cornerstone of precision medicine, leveraging patients’ genomic and proteomic information to diagnose and treat diseases. Many targeted drugs have been approved by the FDA for the diagnosis and treatment of various cancers, while others are in clinical trials (human studies), and more remain in preclinical research (animal studies).

What is the difference between molecular targeted therapy and traditional chemotherapy?
1. Targeted therapy targets specific molecules associated with cancer, whereas chemotherapy kills both rapidly dividing normal cells and cancer cells;
2. Targeted therapy can precisely select or design agents to interact with target receptors, whereas chemotherapy acts merely by broadly killing cells;
3. The targets of targeted therapy are typically cytostatic (inhibiting cell proliferation), whereas traditional chemotherapy is cytotoxic and can kill cancer cells.

How Are Targets Identified for Targeted Therapy?
To achieve targeted effects, it is essential to select the correct targets, namely, to identify key factors in tumor growth and survival.
1. Compare the protein levels in cancer cells with those in normal cells.
Proteins that are absent in normal cells but present exclusively in cancer cells, or abnormally abundant in cancer cells, represent potential targets, indicating overexpression of proteins encoded by mutated genes. A well-known example is the human epidermal growth factor receptor 2 (HER2) protein, which is overexpressed in both breast cancer and gastric cancer cells.

2. Determine whether cancer cells have produced mutated or variant proteins that can promote cancer growth. For example, the cell growth signaling protein BRAF is a mutated protein in melanoma. Vemurafenib (Zelboraf®) targets the mutated BRAF protein and is used to treat unresectable or metastatic melanoma.

3. Identify chromosomal differences between cancer cells and normal cells. Chromosomal abnormalities can give rise to fusion genes, which are formed by joining the coding regions of two or more genes end-to-end to create a chimeric gene. The resulting product is a fusion protein that may promote cancer progression. These fusion genes also serve as therapeutic targets. For example, the drug imatinib mesylate (Gleevec®) targets the BCR-ABL fusion protein, which drives lymphocyte proliferation.

What Are the Types of Targeted Therapy?
1. Hormone Therapy: Leveraging the hormone-dependent nature of certain tumors, this approach delays or halts the growth of hormone-sensitive tumors by inhibiting hormone secretion or interfering with hormonal signaling.
2. Signal Transduction Inhibitors: Block chemical molecules involved in signal transduction to disrupt molecular metabolic pathways.
3. Gene Expression Regulation Method: Regulating key proteins that control gene expression.
4. Apoptosis Inducers: Triggering Apoptosis in Tumor Cells to Eliminate Tumors
5. Immunotherapy: Activating Immune Mechanisms to Destroy Cancer Cells
6. Monoclonal Antibodies Carrying Toxic Molecules: One end of the antibody binds to target cells, while the other carries effector molecules to kill the target cells.

How to Determine Whether a Patient Is Suitable for Targeted Therapy?
For several well-defined cancers, most patients share common actionable targets for targeted therapy. For example, patients with chronic myeloid leukemia (CML) all harbor the BCR-ABL fusion gene as a therapeutic target. For other cancer types, tumor tissues must first be tested to determine whether suitable targets are present.
The premise of targeted therapy is that the patient’s cancer tissue indeed harbors genetic mutations encoding targetable proteins. Patients lacking such mutations are not suitable candidates for targeted therapy, as there is no therapeutic target!
Sometimes, when other treatments are ineffective for cancer patients, or when the cancer has spread and surgery is not an option, targeted therapy may also be attempted. Of course, it must comply with FDA regulations.

Limitations of Targeted Cancer Therapy
1. Drug resistance, development of cancer cell resistance
Resistance develops through two mechanisms: a. mutations in the target itself, leading to failure of targeted therapy; b. tumor cells activate alternative pathways that do not rely on the original target.
Countermeasures: Combine two targeted therapies by selecting two distinct targets within cellular signaling pathways for simultaneous attack; or employ a strategy that combines a single target with one or more chemotherapeutic agents.
Currently, drug resistance is the biggest bottleneck in targeted cancer therapy. Regardless of how effective targeted therapy is initially, most patients develop resistance, and the treatment often loses its efficacy within a year.
2. Due to the complex structure of the targets or their other roles in cells, it is difficult to design drugs to target them.
3. Limited range of treatable conditions; applicable only to a subset of cancer patients.

Side Effects of Targeted Cancer Therapy
1. Causes diarrhea and liver problems, such as hepatitis and elevated liver enzymes
2. Skin issues, such as acne-like rash, dry skin, nail changes, and hair discoloration
3. Coagulation and Wound Healing
4. Hypertension
5. Gastrointestinal perforation (this side effect is relatively rare)
Some side effects also indicate that the patient’s cancer is improving or serve as signs that the treatment is effective.

Classification of Targeted Therapy Drugs
Generally divided into two categories: monoclonal antibodies and small-molecule drugs:
1. Monoclonal Antibodies: The targets are specific antigens on the cell surface, such as transmembrane receptors or extracellular growth factors. In some cases, monoclonal antibodies are conjugated with radioisotopes or toxins, enabling the specific delivery of toxic agents to targeted cancer cells. These monoclonal antibodies are produced by immunizing animals (typically laboratory mice) with purified target proteins. Different antibodies are identified based on the varying phenotypes generated in the experimental animals. Analyses are conducted to determine which antibodies exhibit optimal binding to the target while minimizing cross-reactivity with non-target proteins.

Before monoclonal antibodies can be administered to humans, they must undergo humanization. This process involves recombinant DNA technology to re-express the protein with human sequences derived from murine monoclonal antibody genes. This approach retains the affinity and specificity of the parent murine monoclonal antibody while reducing its immunogenicity, thereby ensuring safe application in humans.

2. Small Molecules: High-throughput sequencing is used to assess the effects of thousands of test compounds on a specific target protein, thereby identifying the most effective small-molecule candidates. Due to their low molecular weight, these compounds can cross cell membranes to enter cells and interact with intracellular targets. They are typically designed to inhibit the enzymatic activity of the target protein while minimizing off-target effects on non-target molecules.

Nomenclature of Molecular Targeted Drugs
Naming: Targeted cancer therapies often have different names. Initially, they are named after the compound under development; if development is successful, the drug is assigned a generic name and a brand name under which the pharmaceutical company markets it. For example, the small molecule STI-571 has the generic name imatinib and was launched by Novartis under the brand name Gleevec™.

Naming Conventions for Generic Names of Targeted Therapy Drugs:

Example:



FDA-Approved Targeted Cancer Therapies (as of February 24, 2015)



Current Issues

Many hospitals and companies perform sequencing only on patients’ tumor tissues to implement personalized medicine, without conducting genetic sequencing on normal tissues—that is, without filtering out the normal cellular variations. This can lead to inappropriate medical interventions. Inevitably, performing the same sequencing on normal cells increases healthcare costs, but it should be an indispensable component.

Examples of New Breakthroughs in 2015
1. EBV-CTL Cytotoxicity Therapy for Malignancies Following Bone Marrow Transplantation Enters Phase II Clinical Trials
2. Pfizer: Ibrance for the Treatment of Breast Cancer
3. Pharmacyclis: Imbruvica for the Treatment of Rare Waldenström's Macroglobulinemia

Hotspots in Targeted Therapy in 2015
1. Immunotherapy: Immune checkpoint inhibitors, represented by anti-PD-1/PD-L1 agents, are expected to gain approval for cancers other than melanoma.
2. Tumor Genomics: Three Major Directions: a. Mechanisms of Cancer Gene Evolution b. Single-Cell Sequencing Advancing the Exploration of Cancer Heterogeneity c. Applications in Clinical Medicine
3. Cancer Prevention: Primarily Immunoprophylaxis or Vaccine-Based Prevention

VCBeat’s Chief Advisor for Analysis of Trending English Terms in Internet Healthcare: Zhao Xinyuan, current CEO of Beijing Yingtai Kelong Technology Co., Ltd., and member of the Technical Guidance Committee of HL7 China.
VCBeat is currently recruiting volunteers to analyze trending English terms in digital health. We welcome you to share your expertise. Please follow the VCBeat WeChat official account and contact us!