L12: Targeted (biological) therapy for cancer

Question 1

What are the advantages of targeted agents / biological therapies?

Answer 1

o Selection biomarkers (can select patients most likely to respond)
o Fewer side effects (‘cancer cell specific)
o Potential for rapid onset of action
o Often oral

Question 2

Describe oestrogen pathway in pre-menopausal women and how it can be targeted.

Answer 2

In pre-menopausal women:
- GnRH stimulates stimulates pituitary gland to release FSH and LH
- They act on ovary to produce estradiol, which then circulates and acts on target tissue, e.g. breast or breast tumour
- You can use surgery to remove this, you can also use GnRH agonists, which bind to GnRH receptors, they bind more tightly, create initial flare, but in the long-term dampens down the production of FSH and LH, and estradiol in the end
- You can also use tamoxifen or fulvestrant, which are selective oestrogen receptor modulators, which bind to ER in target tissue and would block the signalling

Question 3

Describe oestrogen pathway in post-menopausal women and how it can be targeted.

Answer 3

In post-menopausal women:
- They’re not actively producing hormone from ovaries, now produced by other tissues, such as adipose
- They produce oestradiol through aromatase
- Aromatase inhibitors can be used to block that enzyme and stop production of oestradiol

Question 4

Why are aromatase inhibitors not used in pre-menopausal women?

Answer 4

The reason why aromatase inhibitors are not given to pre-menopausal women is that inhibition of aromatase with these inhibitors leads to a feedback loop, where it senses that oestrogen is not being produced, then turns stimulating hormone production even further, which rapidly leads to resistance to this intervention

Question 5

What are CDK4/6 inhibitors? Where are they used?

Answer 5

• palbociclib, ribociclib, abemaciclib
• Used in ER+ Her2- breast cancer with hormone blockade
• G1-to-S cell cycle checkpoint blockade leads to cell cycle arrest

Question 6

What is the toxicity of CDK4/6 inhibitors?

Answer 6

Toxicity:
- Neutropenia (cell cycle arrest of HSCs (hematopoietic stem cells) – easier to manage than chemo)
- Deranged liver function
- Long QT (ribociclib) – heart
- Others include – GI, Renal, alopecia, PE

Question 7

How is majority of prostate cancer driven?

Answer 7

• by overexpression of receptor to testosterone

Question 8

What is the treatment available for prostate cancer?

Answer 8

Treatment:
- GnRH agonists, to reduce production of hormones driving testosterone production
- Can use drugs to block 5alpha reductase enzyme to block production of testosterone to DHT
- You can also inhibit androgen signalling using antagonists (flutamide)

Question 9

What is Glivec? What does it do?

Answer 9

Glivec
- Used to treat BCR/ABL driven lymphoma, where you’ve got fusion of BCR and ABL
- Translocations: BCR/ABL
- Inhibits activity of 3 kinases: bcr-abl, c-KIT and PDGFR
- Glivec is an ATP competitive inhibitor, so it sits in an active site and blocks the binding of ATP and activation of kinase
- Works really well on treatment of CML (Chronic myelogenous leukemia)
- Had no maximum tolerated dose – great thing because, means it’s well tolerated by patients
- Successful clinical trials, became gold standard for BCR-ABL driven leukemia

Question 10

What are the other targets of Glivec?

Answer 10

• Also inhibits c-KIT and PDGF receptor
• Example in gastrointestinal stromal tumours

Question 11

What are gastro-intestinal stromal tumours?

Answer 11

• Tumours that arise from the Cajal cell of the stomach or small bowel
• Chemo/radioresistant
• 95% over-express c-kit, which is a tyrosine kinase molecule very similar to bcr-abl
• Tried using Glivec in GIST – phenomenal response
• First line therapy in unresectable or metastatic GIST

Question 12

What is trastuzumab or herceptin?

Answer 12

HER2: trastuzumab (Herceptin)
- target HER2 in 20-30% of breast cancers – aggressive, chemoresistant, poor-prognosis disease (over-expression transforms cells: homodimer signalling)
- drug: monoclonal antibody (trastuzuMAB) directed against the HER2 receptor (designed to block ligand X, inhibited signalling and growth)
- Humanized: first indication that ADCC may also be important
- Clinical trials: selected patients with HER2+ breast cancer
- Activity: monotherapy and combination activity – both palliative and adjuvant
- Safety: very safe, some cardiac toxicity

Question 13

What is the target of cetuximab? where does it work?

Answer 13

EGFR – antibodies (cetuximab)
- Target here is overexpressed EGFR (c.f. mutation)
- Given to colorectal cancer patients in combination with fluorouracil, leucovorin and oxaliplatin
- Resistance is not via in EGFR, but downstream replacement of the signal (RAS or RAF mutation)
- So only patients with wt KRAS benefit from EGFR inhibition, in KRAS mutants you make it even worse

Question 14

What are gefitinib or erlotinib?

Answer 14

1st generation EGFR tyrosine kinase inhibitors
- Gefitinib and erlotinib
- Often over-expressed and mutated in NSCLC, different to colorectal cancer where it’s just overexpressed
- EGFR-mutation-positive patients do better in treatment with gefitinib, while EGFR-mutation-negative do better with chemo

Question 15

Why does Gefitinib work better in EGFR-mutation-positive patients? Mutated EGFR and lung cancer

Answer 15

First generation EGFR tyrosine kinase inhibitors:
- Such as gefitinib
- ATP mimetics, reversable
- They actually bind better to mutated EGFR
- Mutation L858R increases inhibitor affinity
- Inevitable resistance develops – esp a mutation in exon 20 – T790M, thought to be one of the main reasons why patients become resistant

Question 16

How are EGFR T790M mutations important?

Answer 16

• Confers resistance to standard EGFR inhibitors
• Example of tumour heterogeneity with resistance from a branch mutation
• Can be detected on branches prior to EGFR inhibitor treatment
• Subsequently assumes clonal dominance
• So developed EGFR T790M inhibitors – Osimertinib. Irreversibly binds and inhibits EGFR kinase function

Question 17

How is DNA damage repaired?

Answer 17

• Single strand breaks are repaired by base excision repair pathway, which involves PARP enzyme
• Bulky adducts are repaired by NER
• Base mismatches, insertions and deletion by mismatch repair
• DSBs (cause by chemo or radio) repaired by non-homologous end-joining; can also be repaired by homologous recombination repair pathway, which involves BRCA1/2

Question 18

What are the examples of anti-angiogenics? Where are they used?

Answer 18

• Most angiogenesis – tumour related
• Endothelial cells genetically stale so less likely to acquire resistance
• Target cells (endothelium) easily accessible to blood-borne drugs
• Main target has been the VEGFR:
  o Bevacizumab (binds and sequesters VEGF-A)
   Couple of months benefit in a variety of cancers (eg colorectal ovarian), in combination with standard chemo, take VEGF of circulation, cant induce angiogenesis
  o VEGFR TKIs (sorafenib of sunitinib, pazopanib)
   Renal cancer (far more VEGF than any other cancer)
   Use in other cancers may be related to other tyrosine kinases that are inhibited (e.g. GIST)

Anti-angiogenics – renal cell carcinoma (kidney cancer)
- Chemo-resistant
- Very vascular
- Massive angiogenic (VEGF) signalling
- VEGF inhibitors have improved survival from 1 to 2.5 years

Question 19

Where are bisphosphonates used?

Answer 19

Niches – e.g. bisphosphonates and bone metastases
- Bone metastases are common in cancer (esp breast, prostate)
- Cancer remodels bone and bisphosphonates block this
- This treats pain, increases calcium levels, and prevents fractures