Molecular tumor biology 7.Molecular basics of anti-tumor

therapies 2.Dr. Gábor Mátis

University of Veterinary MedicineDivision of Biochemistry

26 April 2018

Topics of the lecture

The molecular basics of anti-tumor therapies 2.• Irradiation (radiotherapy)• Endocrine therapy• Targeted therapies• Biological therapies – immune therapy• Novel, special therapeutical approaches:

– Photodynamic therapy– Local chemotherapy– Electrochemotherapy– Ultrasound sensitization– Thermotherapy – oncotermia

• Supplemental therapies

Molecular basics of radiotherapy

• Local/regional therapy with ionizing radiation• Types of radiation:

– β radiation = high electrons– ɤ radiation = high energy EM radiation (photons)– α radiation = He nuclei– Neutron radiation

• Quantitative measures: dose Gray (Gy) =J/kg

Comparison of radiation types

Mechanisms of radiotherapy

• Indirect: irradiation energy transmissionionization production of free radicals (ROS)damage of macromolecules (DNA, proteins)

• Direct: irradiation energy transmissiondamage of macromolecules (DNA, proteins) dueto ionization

• Damaged macromolecules inflammation,repair mechanisms apoptosis, loss ofproliferative potential or survival

• Intensively proliferating cells are more sensitiveto oxidative stress selective effects

Mechanisms of radiotherapy

mdpi.com;courses.ecampus.oregonstate.edu

Immune-mediated systemic effects ofradiotherapy

Practical aspects of radiotherapy• Daily therapy is required (fractionated

radiotherapy)• Precise positioning and dosing are important• Veterinary practice: in narcosis• Neoadjuvant, adjuvant or palliative goal

kutyadaganat.com

Side effects of radiotherapy• Local inflammation – skin leasions• Necrotic, fibrotic processes• Periorbital tumors: cornea destruction

todaysveterinarypractice.navc.com

Mechanisms of tumor repopulation afterradiotherapy 1.

Tumor-associated macrophages: NO production nitrosylation of HIF-1αinhibition of VHL binding hypoxia-independent HIF-1α activation

Mechanisms of tumor repopulation afterradiotherapy 2.

Intrinsic pathway of apoptosis activation of caspase 3 activation ofphospholipase A2 arachidonic acid COX-2 PGE2 production

Brachytherapy

Medical Tourism Consultants India; Nick Brook Urology

Endocrine anti-tumor therapy

• Antiestrogens:– Tamoxifen, raloxifen: SERM = selective estrogen receptor modulators

(both agonist and antagonist effects) competing with 17β-estradiol– Fulvestrant: only antagonistic effect

• Gestagens:– Medroxiprogesteron, megestrol: inhibition of FSH, LH, ACTH

production hormone synthesis in ovaries is stopped• Antiprogestinesk: blocking progesteron receptors• Aromatase inhibitors: inhibiting the androstendion estron

reaction (post-menopausal state) – e.g. anastrosol (non-steroid)• GnRH-analogues: agonists (buserelin, goserelin) and antagonists• Androgen blocade: treating prostate cancer

• Molecular diagnostics:– Monitoring (proto-)oncogens and tumor

suppressor genes– Mutations and alterations of gene expression

• More signalling pathways can be involved• Investigating the points of alterations

molecular targets of the therapy

Targeted anti-tumor therapy

Targeted anti-tumor therapy

Targeted therapy: monoclonal antibodies + lowmolecular mass inhibitors

(HER-2 positive mammary tumors)

Trastuzumab HER-2 inhibitionLapatinib tyrosine kinase inhibition

Targeted therapy: monoclonal antibodies + lowmolecular mass inhibitors

– inhibition of VEGF signalling

Bevacizumab VEGFinhibitionSorafenib tyrosinekinase inhibition

alcethron.com; indiamart.com

Targeted therapies – molecular targets

Indian Journal of Pharmacology

Oncogenic pathways and targetedtherapeutical possibilities for

adenocarcinomas

Biological therapy – immune therapy

nanalyze.com

Biological therapy – immune therapy

Photodynamic therapy

sciencedirect.com

Local/regional chemotherapy

• Local vs. systemic (traditional)chemotherapy

• Benefits:– Better efficiency– Reduced side-effects

• Application forms:– Injection into the tumor– Implants

• Biomaterial-based drug-delivery:gelatin, PEG, polyuretane,cellulose, hydrogels…

researchgate.net

Electrochemotherapy

en.wikipedia.org

Electrochemotherapy

cancerres.aacrjournals.org

Sensitization with ultrasound

dev.fusfoundation.org

Thermotherapy – oncothermia

pubs.rsc.org

Supplemental therapies• Antioxidants

– In high dose: prooxidants!– Contraindicated:

• Radiotherapy• Certain types of chemotherapy: e.g.

cisplatin

• Plant extracts, fungi, feedsupplements…– Usually no clear scientific

evidence for efficiency– No magical treatments!

Successful combination of anti-tumortherapeutical modalities

researchgate.net