Chemotherapy- traditional and new targets

• Chemotherapy: Traditional and novel targets
• Cancer


  A disease in a marketplace

  
• Cancer


  • Disease of genes - activating and deactivating mutations
  • Disease of failure of the immune system to recognise cellular change

  
• Immune system


  • Influences the fate of developing cancers
  • As a tumour promoter that facilitates cellular transformation
  • Sculpts tumour cell immunogenicity
  • Extrinsic tumour suppressor that either destroys developing tumours or restrains their expansion

  
• Clinically apparent cancers still arise in immunocompetent individuals in part as a consequence of cancer-induced immunosuppression

  
• Concept to clinic - early testing of candidate drugs

  1. In vitro cell culture

  2. Patient derived xenografts (tumour extracted from patient placed in the skin flap of immunodeficient mice)

  3. Genetically engineered mouse models (animal develops cancer itself, usually mice model but new canine model)

  
• Types of biological therapies

  • Cancer vaccines
  • GFs for blood cells - boost number of DCs
  • IFN and IL2
  • Gene therapy

  
• Strategies for drugs that block cancer blood vessel growth (anti-angiogenesis)

  • Block factors that stimulate angiogenesis
  • Bind the free angiogenic factors
  • Block the effect of angiogenic factors
  • Block the ability of the endothelial cells to break down the surrounding matrix
  • Inhibit normal endothelial cells directly

  
• Drugs


  • VEGF mAb
  • MMP AG3340
• Monoclonal antibodies (mAb)


  • Main types:
  • Trigger the immune system to attack cancer cells
  • Reverse immunosuppressive effect of tumours and allow it to become targeted by the immune cell
  • Stop cancer cells from taking up proteins
  • Prevent interaction with GFs by blocking GFRs
  • Carry cancer drugs or radiation to cancer cells

  
• Monoclonal antibodies


  • Rituximab for non-Hodgkin's lymphoma and some types of leukaemia
  • Bevacizumab for advanced bowel, breast and other cancers
  • Trastuzumab for breast and stomach cancer

  
• Trastuzumab


  • Targets HER2 (human epidermal GFR)
  • About 25-30% of women who have metastatic breast cancer overexpress HER2R
  • Blocking tumour cell growth: The HER2 proteins, with Ab attached, are pulled back into the cell. No HER2 on cell surface > no growth and division
  • Signalling of the immune system: attaches to the HER2 proteins on a tumour cell
  • Working with chemotherapy: Women with HER2 over-expression may not be as responsive to standard breast cancer treatments, including certain regimens of chemotherapy

  
• mAb drug targeting


  • ADEPT for bowel cancer

  
• Radioactivity testing


  • Ibritumomab - in trial for NHL and some other cancers

  
• Cancer growth blockers: Targets

  • EGF - controls cell growth
  • VEGF - controls blood vessel development
  • Platelet derived endothelial GF PDGF - controls blood vessel development and cell growth
  • Fibroblast growth factor FGF - controls cell growth

  
• Cancer growth blockers: Mechanisms

  • Tkis
  • Lmatinib
  • Gefitinib
  • Protease inhibitors
  • MTOR inhibitors
  • PI3K inhibitors
  • Hedgehog pathway blockers
  • Histone de acetyl Kate inhibitors

  
• Chemotherapy: Classes


  • Alkylating agents
  • Antitumour antibiotics
  • Antimetabolites
  • TOPO poisons
  • Spindle-tubule inhibitors
• Alkylating agents


  • Types: Nitrogen mustards, Aziridines, Alkyl alone suffocates, Nitrosourceas, Pt compounds, Non classic agents
  • MOA: Polyfunctional compunds, Alkylation of guanine and interference with DNA replication/transcription to RNA, Cell cycle - phase nonspecific
• Antitumour antibiotics


  • Types: Anthracyclines, Mitomycin C, Bleomycin
  • MOA: Polyfunctional agents, Binds directly to DNA, causing uncoiling/breakage of helix, impairment of DNA and RNA synthesis, Can form free radical to cause damage to DNA, Chelation of important metals, Inhibition of TOPO II
• Antimetabolites


  • Classes: Antifolates: methotrexate, Purine analogues: TG, Pyrimidine analogues: 5FU
  • MOA: Replacing metabolites in key DNA/RNA replication molecules, thereby impairing function, Competing with metabolites at catalytic sites of key enzyme, Competing with metabolites at regulatory sites of key enzyme
• TOPO poisons


  • TOPO I inhibitors: traps the enzyme complex on DNA that then interacts with DNA replication fork causing DNA damage and cell death - Topotecan (prevents revealing of the SSB)
  • TOPO II inhibitors: trap the enzyme complex on DNA and cause cell cycle arrest/death - Etoposide (Due to this, unwinding no longer occurs, causing DSB in the DNA)

  
• Spindle-tubule inhibitors


  • Types: Vinca alkaloids - disruption, Taxanes - prevent disassembly
  • MOA: Prevents the polymerisation / breaking down of microtubules > chromatids during metaphase are not pulled apart > cell cycle arrest
• Drug resistance reversal agents

  • P-glycoprotein and the multi drug resistance - associated protein MRP1
  • Members of the ABC transporter family ABCG2
  • Efflux pump reversing agents relatively non-effective
• Other mechanisms of drug resistance

  • Enhanced DNA repair
  • Changes in cell physiology (hypoxia, pH)
  • Cell cycle changes
  • Loss of ability to engage cell death pathways (e.g. upregulation of BCL2 or dysfunction of p53)

  
• Determinants of drug action

  • Drug characteristics: PK, PD, Metabolisms, Drug-interactions
  • Host characteristics: Performance status, Co-morbidity - low WBC count means certain chemotherapy should not be used, Prior therapies - body condition and appropriateness of new therapy
  • Tumour characteristics: Histology - biomarkers, Target presence and competence, Prior therapies - changes to the TME, Other molecular and biological determinants

  
• Targeting cyclin dependent kinases (CDKs)


  • Rationale: Checkpoint defects distinguish normal cells from tumour cells, thereby providing a potential target for therapeutic intervention
  • No group of regulatory proteins is as intimately coupled to cell progression as the CDKs

  
• Indirect CDK modulators (targeting upstream pathways required for CDK activation)


  • Altering the expression and synthesis of the cyclins, CDKs or CKIs
  • De-methylating agents: When CKI expression has been silenced by methylation, the expression can be restored by demethylating agent such as 5'-deocyazacytidine that prevent promoter methylation
  • Manipulating the proteolytic machinery that regulates the catabolism of CDK or their regulators: Bortezomib - reversibility inhibits proteasome, Promotes apoptosis of tumour cells through the stabilisation of p53, p21, p27 along with Bax, Affects several pathways

  
• Reversing tumour suppressor gene dysfunction

  • Rationale: P53 triggers cell cycle arrest and apoptosis, Inactivated by over expression of mdm-2
  • Nutlins - bind to the p53 pocket on the surface of mdm2 (mimic the interaction of the 2 critical amino acid residues), P53 is stabilised and accumulates, leading to activation of p53 target genes and the p53 pathways, Requires wild type p53 as mutated p53 don't respond to nutlin

  
• Hypoxia


  • Hypoxia inducible factor 1a (HIF1a) is stabilised under hypoxic conditions, which leads to the upregulation of genes involved in cell survival
  • Increased VEGFa production, leading to the formation of abnormal vessels, also contributing to tumour hypoxia
  • Induces poor perfusion and drug delivery

  
• OCT1002 - unidirectional hypoxia activated pro-drug


  • Saturates all tissues, including hypoxic regions but rapidly cleared from oxygenated tissues
  • Designed to be non-toxic and highly penetrant but readily cleared
  • Double dosing with BCA prevented tumour growth
  • Was able to increase pO2 in prostate cancer cells and inhibit metastasis compared to BCA treatment on its own

  
• Right genomic profile


  The right treatment/intervention
• Cancer is a disease of biology
• Cancer


  • Metastasis
  • Proliferation
  • Migration
  • Survival in different signaling environments

  
• Cancer escapes and adapts to a new site

  
• Chemotherapy at the site of origin may not be effective at metastasis site
• Chemotherapy


  • Traditional
  • Novel targets
• Cancer is a disease of failure of the immune system to recognise cellular change

  
• Cancer protects itself from the immune system
• The immune system


  • Influences the fate of developing cancers
  • Can act as a tumour promoter
  • Can promote tumour growth
  • Can sculpt tumour cell immunogenicity
  • Can act as an extrinsic tumour suppressor

  
• Target the immunosuppression so the immune system participates in killing cancer