Teaching pack: Targeted Therapy

Small-molecule kinase inhibitors, monoclonal antibodies, hormone-pathway agents, PARP inhibitors, degraders (PROTACs, molecular glues), and synthetic-lethality approaches. Matched to a molecular alteration by a companion diagnostic. Resistance is the central problem; next-generation and combination strategies are the response.

• Anti-angiogenic therapy: Anti-angiogenic therapy cuts off the tumour's blood supply; it is now mostly used to help immunotherapy work better.
• Antibody-oligonucleotide conjugates: An ADC that carries a gene-silencing strand instead of a chemotherapy, so it can switch a protein off rather than poison the cell.
• Bispecific antibodies: A bispecific antibody is one antibody with two different grabbing arms, so it can block two targets at once or pull an immune cell onto a cancer cell.
• Cancer neuroscience: cutting the nerve supply: Tumours recruit nerves and use nerve signals to grow. Blocking that traffic, with beta-blockers or botulinum toxin, is being tested.
• CDK4/6 inhibitors: Pills that stop the cell-division engine, added to hormone therapy for the most common type of breast cancer.
• De novo designed protein binders: Designing a protein from scratch on a computer to grip a chosen target, instead of finding one in an animal or a library.
• Degrader-antibody conjugate (DAC): An ADC that delivers a protein-destroying molecule instead of chemotherapy, hitting targets inside the cell that were previously unreachable.
• DNA origami nanorobots: Folded DNA machines that open only when they touch a tumour, releasing a payload or clotting the tumour's blood supply.
• Engineered exosomes as drug carriers: Loading the tiny vesicles cells naturally use to talk to each other with a cancer drug, so the body treats the carrier as its own.
• Epigenetic editing (durable gene silencing): Switching a gene off for good without changing the DNA sequence, by writing chemical marks onto it.

• Paths to cures: interception, eradication, control · What already prevents cancer (historic)
• Paths to cures: interception, eradication, control · Vaccinating and monitoring people who do not yet have cancer (emerging)
• Paths to cures: interception, eradication, control · Removing every cell, and knowing that you did (current)
• Paths to cures: interception, eradication, control · Killing the last cell, wherever it is hiding (emerging)
• Paths to cures: interception, eradication, control · Living with cancer as a chronic disease (current)
• Paths to cures: interception, eradication, control · Steering resistance instead of waiting for it (emerging)

• RATIFY (CALGB 10603) (phase 3, n=717): Overall survival (median): 74.7 months vs 25.6 months, HR 0.78
• EXTREME (phase 3, n=442): Overall survival: 10.1 months vs 7.4 months, HR 0.8
• SOLO-1 (phase 3, n=391): Progression-free survival: pending
• LIBRETTO-531 (phase 3, n=291): Progression-free survival at 12 months: 86.8% vs 65.7%, HR 0.28
• MAPS (phase 3, n=448): Overall survival: 18.8 months vs 16.1 months, HR 0.77
• RASolute 302 (phase 3, n=460): Overall survival: 13.2 months vs 6.7 months, HR 0.4

1. What was the first PROTAC ever approved and for what?
   Answer

   Vepdegestrant (Veppanu, Arvinas/Pfizer), an oral oestrogen receptor degrader, approved in 2026 for ESR1-mutated ER+/HER2- advanced breast cancer (VERITAC-2).
2. Which cancer gene was called undruggable for forty years and what changed?
   Answer

   KRAS. In 2013 a covalent pocket was found in the G12C mutant; sotorasib (2021) and adagrasib followed, and pan-RAS(ON) inhibitors such as daraxonrasib are now in phase 3 for pancreatic cancer.
3. What is synthetic lethality and what is the proven clinical example?
   Answer

   Two genes where losing either alone is survivable but losing both kills the cell; tumours with BRCA loss die when PARP is inhibited, the basis of olaparib and other PARP inhibitors.
4. How does a PROTAC differ from a conventional inhibitor?
   Answer

   Rather than blocking a protein's active site it recruits an E3 ubiquitin ligase to tag the protein for destruction by the proteasome, removing the whole protein including scaffolding functions, catalytically and at sub-stoichiometric doses.
5. What is oncogene addiction?
   Answer

   When a cancer depends so completely on one mutated gene that blocking it collapses the tumour, as with EGFR, ALK, BCR-ABL, KIT, and BRAF V600E; dramatic responses then acquired resistance.
6. Name three next-generation ADC concepts beyond bispecific antibodies.
   Answer

   Dual-payload ADCs, degrader-antibody conjugates, immune-stimulating antibody conjugates, masked or conditionally active ADCs, peptide-drug conjugates, radio-ADCs.