Targeted therapy, also called molecularly targeted therapy or molecular therapy, is a form of cancer treatment that uses drugs to target specific molecular changes within a cancer cell that contribute to cancer growth and progression. By targeting these molecular changes, targeted therapy aims to block cancer growth while limiting harm to normal cells. Some common targeted therapies used in oncology include small-molecule inhibitors, monoclonal antibodies, and immune checkpoint inhibitors.
Small-Molecule Inhibitors
Small-molecule inhibitors are oral medications that are designed to inhibit specific enzymes or proteins involved in cancer cell growth and survival. Some examples of molecular targets for small-molecule inhibitors include BCR-ABL, EGFR, HER2, BRAF, and ALK. Imatinib (Gleevec) was one of the earliest small-molecule inhibitors developed to target the BCR-ABL fusion protein in chronic myeloid leukemia (CML). Since then, many other small-molecule inhibitors have been approved to target various gene mutations driving different cancer types. For instance, gefitinib (Iressa) and erlotinib (Tarceva) target EGFR mutations in non-small cell lung cancer, while vemurafenib (Zelboraf) targets BRAF mutations in melanoma.
Monoclonal Antibodies
Monoclonal antibodies are larger protein-based drugs that bind to specific molecular targets on the surface of cancer cells or other cells involved in cancer progression and growth. This binding can result in various effects such as blocking cell surface receptors, activating the immune system, or delivering targeted radiation or chemotherapy to cancer cells. Examples of FDA-approved monoclonal antibodies include trastuzumab (Herceptin) which targets HER2 in breast and gastric cancers, cetuximab (Erbitux) targeting EGFR in colorectal and head/neck cancers, and nivolumab (Opdivo) and pembrolizumab (Keytruda) which target checkpoint proteins PD-1 and PD-L1 to unleash anti-tumor immune responses.
Combination Targeted Therapies
Given the complex nature of cancer, combining different targeted therapies or targeted therapies with traditional chemotherapy is often more effective than single agent treatment. For example, combining trastuzumab and pertuzumab, two anti-HER2 monoclonal antibodies, provides better outcomes than either Oncology Drugs alone in HER2-positive breast cancer. Similarly, pairing a BRAF inhibitor like vemurafenib with a MEK inhibitor like cobimetinib improves survival compared to vemurafenib alone in BRAF mutant melanoma. In lung cancer, combining an EGFR tyrosine kinase inhibitor like erlotinib with the chemotherapy agent bevacizumab was found to delay cancer progression compared to erlotinib alone. Ongoing research continues to explore targeted combination strategies to maximize clinical benefit.
Immunotherapy Approaches
Immunotherapy has revolutionized treatment for many cancer types by augmenting the body's own immune defenses against cancer. Checkpoint inhibitors take the brakes off immune cells by targeting inhibitory receptors like PD-1, PD-L1, and CTLA-4. By blocking these receptors, checkpoint inhibitors allow T cells to mount more robust anti-tumor immune responses. Ipilimumab was the first anti-CTLA-4 antibody to demonstrate improved survival and is now approved for metastatic melanoma. Meanwhile, therapies targeting the PD-1/PD-L1 pathway like nivolumab, pembrolizumab and atezolizumab have shown exceptional promise across lung cancer, head/neck cancers, bladder cancer, Hodgkin's lymphoma, and more.
In addition to checkpoint inhibitors, other immunotherapy approaches include cancer vaccines designed to boost immune responses against specific tumor antigens as well as CAR T-cell therapies that genetically reprogram a patient's T cells to recognize and attack cancer cells. While still new, these therapies have shown remarkable responses in certain blood cancers like leukemia and lymphoma. Overall, immunotherapy has greatly expanded treatment options for patients and achieved durable responses that were previously unheard of. Ongoing work aims to broaden the application of immunotherapy and combine it effectively with other treatment modalities.
Overcoming Resistance
Unfortunately, targeted therapies and immunotherapies are not curative for all patients as resistance mechanisms often emerge over time. Mechanisms of resistance can include new target gene mutations, activation of alternative pathways, immunosuppressive tumor microenvironments, and more. But further research into resistance continues to identify new targets and combination strategies. For example, combining BRAF and MEK inhibitors helped overcome resistance to BRAF inhibitors alone in BRAF-mutant melanoma. Combining EGFR tyrosine kinase inhibitors with angiogenesis inhibitors or chemotherapy may also counter resistance in EGFR-mutant lung cancer. For immunotherapy, combining checkpoint inhibitors that target different immune receptors shows promise to overcome resistance or augment responses. With a deeper understanding of resistance mechanisms on the molecular level, improved patient screening tools, and rational combination treatments, oncologists continue making progress in overcoming resistant disease.
Future Directions
The future of targeted oncology drug development remains promising. Areas of active investigation include developing novel small molecules and biologics against new molecular targets, exploring combination targeted approaches earlier in treatment, developing predictive biomarkers to select patients most likely to benefit, tailoring treatment based on molecular profiling of an individual's tumor, engineering novel CAR T cells against solid tumors, and combining immunotherapy with targeted therapy. With new enabling technologies like next generation sequencing and CRISPR genome editing, cancer researchers now have unprecedented abilities to identify targetable vulnerabilities and develop the next generation of personalized precision oncology treatments
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