2.5 atineoplastic pharmacology

Question 1

Please give an overview of the different pharmacological approaches in oncology.

Answer 1

• cytotoxic chemotherapy
• targeted therapies
• immunotherapies
• endocrine therapies
  + adjuvant therapy to manage ADRs in all cases

Question 2

What are the biological backgrounds for the application of polychemotherapies and cyclic treatments with chemotoxic drugs?

Answer 2

Polychemotherapie
- is needed to excert synergisitic efficacy as they are only cytotoxic in specific phases of the cell cycle wherefore (when alone) they only kill a fraction due to asynchronous cycles
- elimination of cancer cells resistant to single agents
-> reduced dose of every
single drug (less ADR )

The repeating cycles of 1-6 weeks are chosen due to the different cell cycle phases or proliferation rate of the tumor,
depends on tumour biology (proliferation rate) & phase-dependent MOA
–> relative selectivity –> to specifically target the tumor cells and not normal cells
CTx cannot differentiate between cancer cells and normal cells

Question 3

Please discuss possible risk of antioxidative supplements concurrently administered with RTx and/or CTx.

Answer 3

No indications for hypersupplementation, eventhough mirconutrients effect ADRs (Se, Vit B6, Vit B1, Vit D)

Antioxidants like Vit E and Beta-Carotin are concurrent with radiotherapy as they act radioprotective (higher tumour cell survival even at moderate doses of supplements)
-the effect on chemotherapy (CTx) is unclear

-antioxidative pharmaconutrients = tumour protection in RTx; effect on CTx unclear

Question 4

Please discuss the concept of molecular tumour boards as used in state-of-the-art oncology.

Answer 4

Multidisciplinary tumor board as the molecular diagnostic basis for an individualized therapy depending on exome/genome and transcriptome sequencing

Tumor Boards (TBs) are Multidisciplinary Team (MDT) meetings in which different specialists work together closely sharing clinical decisions in cancer care. The composition is variable, depending on the type of tumor discussed. As an organizational tool, MDTs are thought to optimize patient outcomes and to improve care performance.

It is not organ specific like traditional therapy but more molecular targeted

Question 5

Please give examples for molecular targets that are used in so called “targeted cancer therapies“

Answer 5

• monocolonal antibodies target receptor agonists (prevent binding to their receptors)
• small molecules target receptor as an antagonist (block receptor)

eg. phosphoinositide 3 kinases
(PI3Ks),
intracellular signal transducer
enzymes crucial for the
regulation of cellular growth,
differentiation, and survival

Question 6

Please explain the basic MOAs of PI3K inhibitors.

Answer 6

- MOA PI3KI: intracellular signal transducer
enzymes crucial for the
regulation of cellular growth,
differentiation, and survival
- implicated in the
sensitivity of cancer cells
to insulin, IGF-1, and calorie
restriction
- mutated in many cancers
- PI3K activity significantly
contributes to cancer
development & progression

Question 7

Please discuss the possible cross-talk between the PI3K pathways, PI3K inhibitors and nutritional interventions as calorie-restriction, calorie-restriction mimetics and fasting.

Answer 7

• nutrional interventions: Low carb diets boost the effectivness of PI3K Inhibitors as insulin feddbacks (induced by the drug itself) reactivate signaling axis and therby compromise the effect
• CR: induced autophagy through less ActelyCoa (normally inhibitor) which again leads to the inhibition of synthesis/activation of SIRT1 (energy sensor that induces autophagy) as well as less nicotamides
• CRM (Spermidine, Resveratol, Hydroxycitrate): inhibit ATP citrate lyase (AcetylCoa production) or inhibition of EP300 which normally reduces autophagy as it competes with AcetylCoA
• Fasting: autophagy through increased, low IGF1, insulin, glucose, higher IGFBP1 and keton bodies

–> sensitivity of cancer cells to insulin, IGF-1, and calorie restriction

Question 8

Please explain the basic MOAs of checkpoint inhibitors.

Answer 8

• checkpoint inhibitors: monoclonal antibodies from immuno-onocology-therapy
• blockade of negative feedback signalling to immune cells
• -> leads to enhanced immune response against tumour cells
• programmed cell death 1 protein (PD-1)
• PD-1 ligand (= PD-L1)
• cytotoxic T-lymphocyte-associated protein 4 (CTLA-4)