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.
• ATR and CHK1 inhibitors: Drugs that disable the checkpoint cancer cells use to pause and repair DNA under replication stress, pushing tumours with faulty DNA repair into collapse.
• BCL-2 inhibitors: Drugs that switch off BCL-2, the protein that lets cancer cells refuse to die; venetoclax transformed treatment of chronic lymphocytic leukaemia and acute myeloid leukaemia.
• 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.
• Cereblon E3 ligase modulators (CELMoDs): Next-generation relatives of lenalidomide that make the cell's disposal machinery destroy the myeloma proteins Ikaros and Aiolos more completely, working after older drugs fail.
• 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.

• Colorectal cancer roadmap: from the adenoma-carcinoma sequence and the first screening trials to total mesorectal excision, oxaliplatin, RAS testing, immunotherapy for mismatch repair-deficient disease, ctDNA-guided treatment and organ preservation · A cancer with a visible precursor, and the first proof that finding it early saves lives (historic)
• Colorectal cancer roadmap: from the adenoma-carcinoma sequence and the first screening trials to total mesorectal excision, oxaliplatin, RAS testing, immunotherapy for mismatch repair-deficient disease, ctDNA-guided treatment and organ preservation · Total mesorectal excision, and radiotherapy before the operation (historic)
• Colorectal cancer roadmap: from the adenoma-carcinoma sequence and the first screening trials to total mesorectal excision, oxaliplatin, RAS testing, immunotherapy for mismatch repair-deficient disease, ctDNA-guided treatment and organ preservation · Chemotherapy after the operation, and how small the benefit is when the nodes are clear (historic)
• Colorectal cancer roadmap: from the adenoma-carcinoma sequence and the first screening trials to total mesorectal excision, oxaliplatin, RAS testing, immunotherapy for mismatch repair-deficient disease, ctDNA-guided treatment and organ preservation · The screening programmes, and the discovery that uptake is the whole game (current)
• Colorectal cancer roadmap: from the adenoma-carcinoma sequence and the first screening trials to total mesorectal excision, oxaliplatin, RAS testing, immunotherapy for mismatch repair-deficient disease, ctDNA-guided treatment and organ preservation · Antibodies, and the two things that decide whether they work (current)
• Colorectal cancer roadmap: from the adenoma-carcinoma sequence and the first screening trials to total mesorectal excision, oxaliplatin, RAS testing, immunotherapy for mismatch repair-deficient disease, ctDNA-guided treatment and organ preservation · The genome, the subtypes and the hypermutated sixth (historic)
• Gallbladder cancer roadmap: from a chance finding at gallstone surgery to a disease with its own trials · Surgery arrives, and the cancer is found by accident (historic)
• Gallbladder cancer roadmap: from a chance finding at gallstone surgery to a disease with its own trials · Staging by depth, then by side (historic)
• Gallbladder cancer roadmap: from a chance finding at gallstone surgery to a disease with its own trials · The incidental cancer pathway: re-resect from T1b, but who, when and how much (current)
• Gallbladder cancer roadmap: from a chance finding at gallstone surgery to a disease with its own trials · A borrowed chemotherapy standard (historic)
• Gallbladder cancer roadmap: from a chance finding at gallstone surgery to a disease with its own trials · Adjuvant capecitabine and second-line FOLFOX, from UK trials (current)
• Gallbladder cancer roadmap: from a chance finding at gallstone surgery to a disease with its own trials · Radiotherapy: one single-arm trial and a nomogram (historic)
• KRAS roadmap: undruggable → G12C → pan-RAS · Discovery and failure (historic)
• KRAS roadmap: undruggable → G12C → pan-RAS · The switch-II pocket (historic)
• KRAS roadmap: undruggable → G12C → pan-RAS · Beyond G12C (current)
• KRAS roadmap: undruggable → G12C → pan-RAS · Approval and combinations (emerging)
• KRAS roadmap: undruggable → G12C → pan-RAS · Speculative (speculative)
• Lung cancer roadmap: from Doll and Hill and the naming of tobacco, through the cytotoxic plateau, computed tomography screening, EGFR and ALK, immunotherapy by PD-L1, the perioperative trials and PACIFIC, to DLL3 in small-cell disease and a 2032 registry watch · The cause is named, and cancer epidemiology is invented to name it (historic)
• Lung cancer roadmap: from Doll and Hill and the naming of tobacco, through the cytotoxic plateau, computed tomography screening, EGFR and ALK, immunotherapy by PD-L1, the perioperative trials and PACIFIC, to DLL3 in small-cell disease and a 2032 registry watch · Cytotoxic chemotherapy, and the ceiling it hit (historic)
• Lung cancer roadmap: from Doll and Hill and the naming of tobacco, through the cytotoxic plateau, computed tomography screening, EGFR and ALK, immunotherapy by PD-L1, the perioperative trials and PACIFIC, to DLL3 in small-cell disease and a 2032 registry watch · EGFR, ALK, and the invention of precision oncology in solid tumours (historic)
• Lung cancer roadmap: from Doll and Hill and the naming of tobacco, through the cytotoxic plateau, computed tomography screening, EGFR and ALK, immunotherapy by PD-L1, the perioperative trials and PACIFIC, to DLL3 in small-cell disease and a 2032 registry watch · Low-dose computed tomography earns its place, and chest radiography loses its (historic)
• Lung cancer roadmap: from Doll and Hill and the naming of tobacco, through the cytotoxic plateau, computed tomography screening, EGFR and ALK, immunotherapy by PD-L1, the perioperative trials and PACIFIC, to DLL3 in small-cell disease and a 2032 registry watch · Immunotherapy, and the trouble with PD-L1 as a gate (historic)
• Lung cancer roadmap: from Doll and Hill and the naming of tobacco, through the cytotoxic plateau, computed tomography screening, EGFR and ALK, immunotherapy by PD-L1, the perioperative trials and PACIFIC, to DLL3 in small-cell disease and a 2032 registry watch · Stage III, and treatment moving to either side of the operation (current)
• Lymphoma roadmap: from a jaw tumour in Uganda and the first human cancer virus to gene-expression subtypes, PET-adapted chemotherapy, CAR-T cells, bispecific antibodies and the genetics-directed trials now recruiting · Two viruses, found because lymphoma is the cancer you can get hold of (historic)
• Lymphoma roadmap: from a jaw tumour in Uganda and the first human cancer virus to gene-expression subtypes, PET-adapted chemotherapy, CAR-T cells, bispecific antibodies and the genetics-directed trials now recruiting · How little is enough: the Hodgkin de-escalation programme begins (historic)
• Lymphoma roadmap: from a jaw tumour in Uganda and the first human cancer virus to gene-expression subtypes, PET-adapted chemotherapy, CAR-T cells, bispecific antibodies and the genetics-directed trials now recruiting · Reading the genes, and the twenty years it took to make that useful (historic)
• Lymphoma roadmap: from a jaw tumour in Uganda and the first human cancer virus to gene-expression subtypes, PET-adapted chemotherapy, CAR-T cells, bispecific antibodies and the genetics-directed trials now recruiting · Everything that failed to beat R-CHOP, and the one thing that did (current)
• Lymphoma roadmap: from a jaw tumour in Uganda and the first human cancer virus to gene-expression subtypes, PET-adapted chemotherapy, CAR-T cells, bispecific antibodies and the genetics-directed trials now recruiting · The scan after two cycles, and what it is good for (current)
• Lymphoma roadmap: from a jaw tumour in Uganda and the first human cancer virus to gene-expression subtypes, PET-adapted chemotherapy, CAR-T cells, bispecific antibodies and the genetics-directed trials now recruiting · Indolent lymphoma: how long to treat, and the two-year mark that splits the disease (current)
• Pancreatic cancer roadmap: from Whipple's operation to gemcitabine, FOLFIRINOX, adjuvant chemotherapy, PARP inhibition, KRAS inhibition, vaccines and the surveillance question · One operation, and still the only cure (historic)
• Pancreatic cancer roadmap: from Whipple's operation to gemcitabine, FOLFIRINOX, adjuvant chemotherapy, PARP inhibition, KRAS inhibition, vaccines and the surveillance question · A blood marker with a blind spot and an oncogene in nearly every tumour (historic)
• Pancreatic cancer roadmap: from Whipple's operation to gemcitabine, FOLFIRINOX, adjuvant chemotherapy, PARP inhibition, KRAS inhibition, vaccines and the surveillance question · Gemcitabine, and chemotherapy after surgery (historic)
• Pancreatic cancer roadmap: from Whipple's operation to gemcitabine, FOLFIRINOX, adjuvant chemotherapy, PARP inhibition, KRAS inhibition, vaccines and the surveillance question · Combination chemotherapy for metastatic disease (historic)
• Pancreatic cancer roadmap: from Whipple's operation to gemcitabine, FOLFIRINOX, adjuvant chemotherapy, PARP inhibition, KRAS inhibition, vaccines and the surveillance question · Genomes, subtypes and the inherited five percent (historic)
• Pancreatic cancer roadmap: from Whipple's operation to gemcitabine, FOLFIRINOX, adjuvant chemotherapy, PARP inhibition, KRAS inhibition, vaccines and the surveillance question · Adjuvant modified FOLFIRINOX, and the neoadjuvant question (current)
• 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)
• Prostate cancer roadmap: from Huggins and the discovery that a cancer can depend on a hormone, through the PSA epidemic and what it cost, the androgen receptor drugs, the DNA repair subset and PSMA, to a 2032 registry watch · A cancer is shown to depend on a hormone, and systemic cancer therapy begins (historic)
• Prostate cancer roadmap: from Huggins and the discovery that a cancer can depend on a hormone, through the PSA epidemic and what it cost, the androgen receptor drugs, the DNA repair subset and PSMA, to a 2032 registry watch · A blood test arrives, and an epidemic of diagnoses follows it (historic)
• Prostate cancer roadmap: from Huggins and the discovery that a cancer can depend on a hormone, through the PSA epidemic and what it cost, the androgen receptor drugs, the DNA repair subset and PSMA, to a 2032 registry watch · Does treating localised disease help? Three trials, three answers, one rule (historic)
• Prostate cancer roadmap: from Huggins and the discovery that a cancer can depend on a hormone, through the PSA epidemic and what it cost, the androgen receptor drugs, the DNA repair subset and PSMA, to a 2032 registry watch · The screening trials disagree, and the policy swings twice (historic)
• Prostate cancer roadmap: from Huggins and the discovery that a cancer can depend on a hormone, through the PSA epidemic and what it cost, the androgen receptor drugs, the DNA repair subset and PSMA, to a 2032 registry watch · Chemotherapy works, a little, and then the receptor drugs arrive (historic)
• Prostate cancer roadmap: from Huggins and the discovery that a cancer can depend on a hormone, through the PSA epidemic and what it cost, the androgen receptor drugs, the DNA repair subset and PSMA, to a 2032 registry watch · The genome: a quiet sequence, a rearranged structure, and one actionable fifth (historic)
• Targeted therapy roadmap: imatinib → designed for resistance → the undruggable drivers fall · The idea of a target (historic)
• Targeted therapy roadmap: imatinib → designed for resistance → the undruggable drivers fall · Oncogene addiction, and the resistance lesson (historic)
• Targeted therapy roadmap: imatinib → designed for resistance → the undruggable drivers fall · Designed for resistance, the brain and the adjuvant setting (current)
• Targeted therapy roadmap: imatinib → designed for resistance → the undruggable drivers fall · The undruggable drivers fall (current)
• Targeted therapy roadmap: imatinib → designed for resistance → the undruggable drivers fall · Fourth generations, degraders and switching on a blood test (emerging)
• Targeted therapy roadmap: imatinib → designed for resistance → the undruggable drivers fall · New modalities for the old targets (emerging)
• Triple-negative breast cancer roadmap: from a remainder defined by three negative tests to immunotherapy, antibody-drug conjugates and the residual disease problem · Defined by three negative tests (historic)
• Triple-negative breast cancer roadmap: from a remainder defined by three negative tests to immunotherapy, antibody-drug conjugates and the residual disease problem · The basal-like subtype and its link to BRCA1 (historic)
• Triple-negative breast cancer roadmap: from a remainder defined by three negative tests to immunotherapy, antibody-drug conjugates and the residual disease problem · Founder mutations: hereditary disease has a geography (historic)
• Triple-negative breast cancer roadmap: from a remainder defined by three negative tests to immunotherapy, antibody-drug conjugates and the residual disease problem · A name, a natural history and a disparity (historic)
• Triple-negative breast cancer roadmap: from a remainder defined by three negative tests to immunotherapy, antibody-drug conjugates and the residual disease problem · Anthracycline and taxane chemotherapy, and the residual disease paradox (historic)
• Triple-negative breast cancer roadmap: from a remainder defined by three negative tests to immunotherapy, antibody-drug conjugates and the residual disease problem · Several diseases: molecular subtypes (historic)

• VELOUR (phase 3, n=1,226): Overall survival: 13.5 months vs 12.06 months, HR 0.817
• PARADIGM (phase 3, n=823): Overall survival, left-sided: 37.9 months vs 34.3 months, HR 0.82
• PRIME (phase 3, n=1,183): Overall survival (RAS wild-type): 26 months vs 20.2 months, HR 0.78
• CORRECT (phase 3, n=760): Overall survival: 6.4 months vs 5 months, HR 0.77
• FRESCO-2 (phase 3, n=691): Overall survival: 7.4 months vs 4.8 months, HR 0.66
• RAINBOW (phase 3, n=665): Overall survival: 9.6 months vs 7.4 months, HR 0.81

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.

• NCI: Targeted therapy to treat cancer: https://www.cancer.gov/about-cancer/treatment/types/targeted-therapies