Bioreductive drugs and hypoxic cell sensitizers

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Lecture by Prof. Kayne Williams in the context of the Course: "Tumour Hypoxia: From Biology to Therapy III".
For the complete e-Course see http://www.myhaikuclass.com/MaastroClinic/metoxia

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  • Really useful overview emphasing the presence of tumour hypoxia in all, or almost all, solid tumours and the implications of tumour hypoxia for poor prognosis. In particular Professor Williams focusses on of the importance of targeting the hypoxic tumour cells with drugs that are designed to specifically kill these cells.
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Bioreductive drugs and hypoxic cell sensitizers

  1. 1. METOXIA CourseBioreductive drugs and hypoxic cell sensitisers Kaye Williams 12th October 2012 This course is funded with the support of the METOXIA project under the FP7 Programme.
  2. 2. Conventional chemotherapy Chemotherapy is the use of drugs that kill rapidly dividing cells to treat cancer. Chemotherapy drugs are toxic to cancer cells, which take in the drugs as they multiply. Once inside the cells, the drug kills the cell or prevents it from dividing and forming new cells. This course is funded with the support of the METOXIA project under the FP7 Programme.
  3. 3. Conventional chemotherapy: problems Chemotherapy is associated with a number of side effects, mainly because chemotherapy drugs are toxic to all actively dividing cells, not just cancer cells. Cells in the bone marrow, the lining of the stomach and intestines, and the hair follicles are normally actively dividing. Therefore, chemotherapy may result in a decrease in blood cell counts, nausea, vomiting, diarrhoea, and loss of hair. This course is funded with the support of the METOXIA project under the FP7 Programme.
  4. 4. Molecular targeted therapies Targeted cancer therapies use drugs that block the growth and spread of cancer by interfering with specific molecules involved in carcinogenesis and tumour growth Many of these therapies focus on proteins that are involved in the signalling processes that regulate tumourigenesis. Different classes of agent are in development or licensed, including small molecule inhibitors and antibodies This course is funded with the support of the METOXIA project under the FP7 Programme.
  5. 5. FDA approved molecular targeted therapies signal transduction inhibitors (Gleevec®, gastrointestinal stromal tumour and chronic myeloid leukemia; Iressa® non- small cell lung cancer) apoptosis (cell death)-inducing agents (Velcade®, multiple myeloma) anti-angiogenics (Avastin®; colorectal carcinoma). This course is funded with the support of the METOXIA project under the FP7 Programme.
  6. 6. Targeting the tumour microenvironment- hypoxia Normal tissues: Hypoxia is rare Median O2 concentration 3.1% to 8.7% Solid tumours: Hypoxia is common Greater than 80% of O2 readings below 0.3% Hypoxia is a tumour-specific condition that can be exploited in cancer therapy This course is funded with the support of the METOXIA project under the FP7 Programme.
  7. 7. How hypoxia develops in tumours This course is funded with the support of the METOXIA project under the FP7 Programme.
  8. 8. Dynamic fluctuations in tumour perfusion Hoechst Carbocyanin This course is funded with the support of the METOXIA project under the FP7 Programme.
  9. 9. Why target tumour hypoxia? Regions of low oxygen present in majority of solid tumours Hypoxic cells are viable and resistant to some forms of chemotherapy and to radiotherapy Hypoxia drives genetic instability and is associated with an aggressive disease phenotype This course is funded with the support of the METOXIA project under the FP7 Programme.
  10. 10. Significance of tumour hypoxiaChronic Radioresistance Acute Radiation Dose (Gy) Chemoresistance Aggressive phenotype 1 HT29 0.1 Promotion of genomic 0.01 100 200 300 400 500 instability 0.001 Oxic Hypoxic 0.0001 Etoposide (mM) This course is funded with the support of the METOXIA project under the FP7 Programme.
  11. 11. Targeting the tumour microenvironment A defining characteristic of all solid tumours analysed to date is the presence of hypoxia (low oxygen) Capillary Drug concentration Proliferation Normal oxygen Nutrition Oxygen Low oxygen (hypoxia) Aggressive disease phenotype Resistance to Necrosis therapy (death) This course is funded with the support of the METOXIA project under the FP7 Programme.
  12. 12. Low oxygen tension is present in all solid tumours and is associated with treatment failure HYPOXIA Oxygen effect Gene expression Hypoxia induced transcription factors/Hypoxia-selective prodrugs downstream effector molecules Molecular targeted therapies This course is funded with the support of the METOXIA project under the FP7 Programme.
  13. 13. Oxygen availability drives cellular response to radiotherapy Indirect action dominant for x-rays Direct action Image taken from Horsman and Overgaard in Basic Clinical Radiobiology (Ed. Steel) This course is funded with the support of the METOXIA project under the FP7 Programme.
  14. 14. The dependence of radiosensitivity on oxygen concentration 3Relative radiosensitivity Air 100% 2 oxygen 3mm Hg or 0.5% 1 10 20 30 40 50 60 70 155 760 Oxygen tension (mm Hg at 37 C) This course is funded with the support of the METOXIA project under the FP7 Programme.
  15. 15. Strategies to overcome tumour hypoxia: hypoxic cell radiosensitisers• Electron-affinic chemicals that mimic oxygen in fixing free- radical damage• Hypoxic cell sensitisers are not metabolised by the cells in the tumour through which they diffuse• Consequently, hypoxic cell sensitisers can penetrate further than oxygen and reach all hypoxic cells in the tumour This course is funded with the support of the METOXIA project under the FP7 Programme.
  16. 16. Radiation-response as a function of misonidazole administration pre- or post- radiation treatmentC3H mouse mammary tumour measured 120 days after irradiation This course is funded with the support of the METOXIA project under the FP7 Programme. Overgaard and Horsman, 1993
  17. 17. Development of nitroimidazoles as hypoxic cell radiosensitisersMetronidazoleMisonidazole: more active, toxic (CNS toxicity dose limiting); benefit in some cancer sub-groupsEtanidazole: equal activity to misonidazole, less toxic; no clinical benefitNimorazole: less active, markedly less toxic; benefit in head- and-neck cancer This course is funded with the support of the METOXIA project under the FP7 Programme.
  18. 18. Actuarial estimated loco-regional tumour control in patients randomised to receive nimorazole or placebo in conjunction with conventional radiotherapy for carcinoma of the pharynx and supraglottic larynx. This course is funded with the support of the METOXIA project under the FP7 Overgaard et al., 1998 Programme.
  19. 19. Current Phase 3 nimorazole trial: IAEA-HypoX. Accelerated Radiotherapy With or Without Nimorazole in Squamous Cell Carcinoma of the Head and NeckDanish Head and Neck Cancer Group• Primary Outcome Measures: Locoregional control after curative intended radiotherapy +/- Nimorazole• Secondary Outcome Measures: Disease specific survival• Overall survival• Treatment related morbidity: Treatment related acute and late morbidity related to radiotherapy and/or nimorazole treatment This course is funded with the support of the METOXIA project under the FP7 Programme.
  20. 20. Bioreductive drugs- hypoxic selective cytotoxins Rationale: “Exploit the reductive environment of tumours by developing drugs that are reduced preferentially to cytotoxic species in the hypoxic regions of tumours”Use in combination with agents that preferentially kill oxic cells Activity depends not only on presence of hypoxia within a cell but also upon the complement of reductase enzymes This course is funded with the support of the METOXIA project under the FP7 Programme.
  21. 21. Classes of bioreductive agents• Quinone antibiotics eg mitomycin C• Nitroaromatics eg RSU1069 (developed from the hypoxic-cell sensitiser misonidazole - normal tissue cytoxicity prevented clinical usage); NLCQ-1• di-N-oxides eg tirapazamine, AQ4N This course is funded with the support of the METOXIA project under the FP7 Programme.
  22. 22. Simplified schematic of bioreductive drug activation 1 e - reductase mediatedProdrug Toxic species - .- 02 02 This course is funded with the support of the METOXIA project under the FP7 Programme.
  23. 23. Intermediate O2 level 1 tirapazamine Surviving fraction 0.1 AQ4N NLCQ-1 RB6145/RSU1069 radiation 0.01 0.1 1 10 100 Oxygen partial pressure (mmHg) This course is funded with the support ofReference: C.J.Koch (1993) the METOXIA project under the FP7Cancer Research 53:3992-3997 Programme.
  24. 24. Prodrug Cytotoxic species Final product Enzymes thought responsibleBenzotriazine Free radical (SR4317) Non-toxic (SR4330) P450R; iNOSe.g. TirapazamineBi (and mono) functional DNA-adduct Non-functional P450R; DTDalkylating agents reduced druge.g. MMC, porfiromycin,RB 6145, E09Alkyl-amino- AQ4 Stable persistent Cytochrome P450s: 1A1,Anthraquinones cytotoxin 2B6, 3A4; iNOSe.g. Banoxantrone (AQ4N)NLCQ-1 Nitro (1ee), nitroso (2ee) Unknown, shows Cytochrome b5, other one and hydroxylamine (4ee) weak electron reductases metabolites DNA-intercalating activityPhosphate esters of Stable cytotoxin Stable persistent Phosphatases to generatedinitrobenzamide cytotoxin alcohol then nitro-mustards e.g. PR-104 reductases, including one-(Proacta) electron reductases McKeown SR, Cowen This course is funded with the support of RL, Williams KJ. Clinical the METOXIA project under the FP7 Programme. Oncology, 19, 427-442 (2007).
  25. 25. Influence of hypoxia on the response of KHT murine tumour cells to RSU1069 or tirapazamine RSU1069 Tirapazamine Air Air Anoxia Anoxia This course is funded with the support of the METOXIA project under the FP7 Programme.
  26. 26. Effect of TPZ treatment on radiation response of SCCVII mouse carcinoma: growth delay TPZ Saline X-ray aloneTumour volume (mm3) 103 TPZ+ x-ray X-ray +TPZ 102 8x2.5Gy 101 0 25 50 Days after first treatment This course is funded with the support of the METOXIA project under the FP7 Brown et al, Int.J.Radiat. Oncol. Biol. Programme. Phys, 20, 457-461, 1991
  27. 27. In vivo activation of the hypoxia-targeted cytotoxin AQ4N (banoxantrone) in human tumour xenograftsPre-clinical validation of methods for detecting AQ4 in tumour samples that have subsequently been used in clinical trials Calu-6 24h post 60mg/kg AQ4N Glut-1 AQ4 RT112 RT112 Calu-6 AQ4 AQ4 AQ4N Standards AQ4N Standards Control 50mm Untreated control tumour 16mm Williams KJ*, Albertella MR*, et al. Mol Cancer Therapeutics, 8, 3266-3275 (2009). This course is funded with the support of the METOXIA project under the FP7 Programme.
  28. 28. AQ4N enhances chemo-radiotherapy in human tumour xenografts 1200 1200 1200 1200 800 800 800 800Tumour volume (mm3) 400 400 400 400 10 x 2 Gy 10 x 2 Gy AQ4N 00 00 0 20 40 60 80 0 40 80 0 0 20 40 40 60 80 80 1200 1200 1200 1200 800 800 800 800 400 400 400 400 10 x 2 Gy 10 x 2 Gy Cisplatin AQ4N +Cis 00 00 0 20 40 60 80 0 20 40 60 80 0 40 80 0 40 80 Time (days) Williams KJ*, Albertella MR*, et al. Mol Cancer Therapeutics, 8, 3266-3275 (2009). This course is funded with the support of the METOXIA project under the FP7 Programme.
  29. 29. Phase III Trial data: Tirapazamine plus cisplatin versus cisplatin alone in non-small cell lung cancer Cisplatin Tirapazamine+cisplatinNumber patients 218 219Total responders 30 (13.7%) 60 (27.5%) This course is funded with the support of the METOXIA project under the FP7 Programme.
  30. 30. Phase I/II Trial data: concurrent tirapazamine, cisplatin and radiotherapyPhase I/II: Locally advanced cervical cancer, 6 month follow-up: • complete pelvic control of disease in 13 out of 15 patients treated (87%) • suggested better efficacy than standard regimes that achieve 70-75% control rates at 6 months Craighead et al, Int J Rad Onc Biol Phys, 48, 791-795, 2000Phase I: Advanced head and neck cancer: • 3-year local progression free rate 88% reported although trial was not designed to evaluate efficacy Rischin et al,J Clin Oncol, 19, 535-542, 2001 This course is funded with the support of the METOXIA project under the FP7 Programme.
  31. 31. Tirapazamine, cisplatin, and radiation versus cisplatin and radiation for advanced squamous cell carcinoma of the head and neck (TROG 02.02, HeadSTART): a phase III trial of the Trans-Tasman Radiation Oncology Group.PATIENTS AND METHODS:Patients with previously untreated stage III or IV head and neck cancersTreatment:1. Radiotherapy (70 Gy in 7 weeks) concurrently with CIS (100 mg/m(2)) on day 1 of weeks 1, 4, and 7 (CIS)2. Radiotherapy (70 Gy in 7 weeks) concurrently with CIS (75 mg/m(2)) plus TPZ (290 mg/m(2)/d) on day 1 of weeks 1, 4, and 7 and TPZ alone (160 mg/m(2)/d) on days 1, 3, and 5 of weeks 2 and 3 (TPZ/CIS).The primary end point was overall survival (OS). This course is funded with the support of Rischin D, et al J Clin Oncol. the METOXIA project under the FP7 2010;28 :2989-95. Programme.
  32. 32. TROG 02.02, HeadSTARTRESULTS:• Eight hundred sixty-one patients were accrued from 89 sites in 16 countries.• In an intent-to-treat analysis, the 2-year OS rates were 65.7% for CIS and 66.2% for TPZ/CIS (TPZ/CIS--CIS: 95% CI, -5.9% to 6.9%).• There were no significant differences in failure-free survival, time to locoregional failure, or quality of life.CONCLUSIONS: We found no evidence that the addition of TPZ to chemoradiotherapy, in patients with advanced head and neck cancer not selected for the presence of hypoxia, improves OS. This course is funded with the support of the METOXIA project under the FP7 Programme.
  33. 33. Critical impact of radiotherapy protocol compliance and quality in the treatment of advanced head and neck cancer: results from TROG 02.02.PURPOSE: To report the impact of radiotherapy quality on outcome in alarge international phase III trial evaluating radiotherapy withconcurrent cisplatin plus tirapazamine for advanced head and neckcancer.PATIENTS AND METHODS: The protocol required interventional reviewof radiotherapy plans by the Quality Assurance Review Center (QARC).All plans and radiotherapy documentation underwent post-treatmentreview by the Trial Management Committee (TMC) for protocolcompliance.Secondary review of noncompliant plans for predicted impact on tumorcontrol was performed. This course is funded with the support of Peters LJ, et al J Clin Oncol. the METOXIA project under the FP7 Programme. 2010; 28:2996-3001.
  34. 34. Critical impact of radiotherapy protocol compliance ….. RESULTS:  25.4% of the patients had noncompliant plans  47% of noncompliant plans (12% overall) had deficiencies with a predicted major adverse impact on tumor control.  Major deficiencies were highly correlated with number of patients enrolled at the treatment center (less patients, worse RT)  In patients who received at least 60 Gy, those with major deficiencies (n = 87) had a markedly inferior outcome compared with those whose treatment was initially protocol compliant. These results demonstrate the critical importance of radiotherapyquality on outcome of chemoradiotherapy in head and neck cancer.Centers treating only a few patients are the major source of quality problems. This course is funded with the support of Peters LJ, et al J Clin Oncol. the METOXIA project under the FP7 Programme. 2010; 28:2996-3001.
  35. 35. Tirapazamine failure • Poorly given radiotherapy • Poorly managed drug toxicity • No patient selection based on tumour hypoxiaCohorts of patients with hypoxic tumours that could have been benefiting from the treatment would not be easily identified This course is funded with the support of the METOXIA project under the FP7 Programme.
  36. 36. Tirapazamine is not an ideal drug- it has poor biodistributionChronic hypoxia necrosis RB6145/NLCQ-1 TPZ Intermediate hypoxia O2 Normoxia
  37. 37. New Tirapazamine analogues for clinical development- SN30000 Drug passing through-Multicellular layer model TPZ is worst SN30000 SN29751 TPZ Hicks et al Clin Cancer Res. 2010 This course is funded with the support of the METOXIA project under the FP7 Programme.
  38. 38. Summary • Hypoxic cells are found in all solid tumours • Hypoxic cells cause resistance to radio and mainly types of chemotherapy • Hypoxic cells can be targeted • Classic radiosesnitisers mimic the affect of oxygen- nimorazole shows clinical benefit • Bioreductive drugs are selectively toxic towards hypoxic cells • Phase II data has shown promise, but Phase III trials disappointing- need to select patients with hypoxic tumours and manage RT and drug appropriately • New bioreductives are entering the clinic:Need to ensure we get the right drugs in to the patients that are most likely to benefit to ensure failure of TPZ is not repeated This course is funded with the support of the METOXIA project under the FP7 Programme.

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