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Journal reading

Journal reading. 報告者： PGY2 曾智皇 報告日期 : 103.06.10 指導老師 : 林立民 醫師 陳玉昆 醫師. Introduction CA-IX expression and prognosis in OSCC CA-IX expression in other HNSCCs Relationship between CA-IX and chemoresistance or radioresistance The relationship between CA-IX and other molecules

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Journal reading

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  1. Journal reading 報告者：PGY2 曾智皇 報告日期 : 103.06.10 指導老師 : 林立民 醫師 陳玉昆 醫師

  2. Introduction • CA-IX expression and prognosis in OSCC • CA-IX expression in other HNSCCs • Relationship between CA-IX and chemoresistance or radioresistance • The relationship between CA-IX and other molecules • Role of CA-IX as therapeutic target against cancer • Conclusions

  3. Introduction • CA-IX expression and prognosis in OSCC • CA-IX expression in other HNSCCs • Relationship between CA-IX and chemoresistance or radioresistance • The relationship between CA-IX and other molecules • Role of CA-IX as therapeutic target against cancer • Conclusions

  4. Introduction • Hypoxia and tumor cell proliferation determine response to surgery, CT, and RT • Tumor hypoxia  • The promotion of genetic instability • The invasive capacity of tumor cells • Metastasis • Worsening of the clinical evolution  loss of the apoptotic capacity of cells

  5. Among the hypoxia markers, we will focus on the exogenous hypoxia markers, mainly 2-nitroimidazole, pimonidazole, and EF-5 • In addition to exogenous markers, there are endogenous hypoxia markers, controlled by hypoxia-related genes, formed by HIF-1

  6. HIF-1  • Related to the von Hippel-Lindau (vHL) tumor suppressor protein during oncogenesis • Controls several target genes that involve the energy metabolism, angiogenesis (VEGF) and transmembrane carbonic anhydrases (CAs)

  7. CAs are transmembrane Zn metalo-enzymes • catalyze reversible hydration of carbon dioxide in carbonic acid • involved in respiration and acid-base equilibrium • CA-IX and CA-XII are the two tumor-related carbonic anhydrases

  8. CA-IX is largely expressed in tumor cell lines and shows moderate-low expression in a healthy gastrointestinal tract • CA-IX expression has been thoroughly described in different tumors  however, this has not been so for head and neck carcinomas

  9. Introduction • CA-IX expression and prognosis in OSCC • CA-IX expression in other HNSCCs • Relationship between CA-IX and chemoresistance or radioresistance • The relationship between CA-IX and other molecules • Role of CA-IX as therapeutic target against cancer • Conclusions

  10. Introduction • CA-IX expression and prognosis in OSCC • CA-IX expression in other HNSCCs • Relationship between CA-IX and chemoresistance or radioresistance • The relationship between CA-IX and other molecules • Role of CA-IX as therapeutic target against cancer • Conclusions

  11. Hoogsteen et al 2005  a. Analyzed CA-IX expression and IdUrd in a series of 60 HNSCC cases, including 3 OSCC cases b. Joint expression of CA-IX and IdUrd responsible for repopulation and disease progression

  12. Le et al 2007 • Elevated correlation of hypoxia levels and CA-IX • CA-IX  not related to any of the prognostic variables

  13. Kaanders et al 2002 • Studied distribution of pimonidazole and CA-IX • Patients with hypoxic tumors and low vascular density showed worse locoregional control Although no relation was found between CA-IX expression and treatment outcome

  14. HNSCCs  • Hypoxic tumors by definition • Frequently diagnosed in very advanced stages • In HPV-positive cases that normally have better prognosis

  15. Brockton et al 2011 Showed that a high stromal expression of CA-IX is related to a reduced average survival in p16-negative tumors • Kong et al 2009 • 44% (36 of 82) HNSCC cases under study presented a strong HPV pyrosequencing signal • No relation with tumor hypoxia and CA-IX expression

  16. Introduction • CA-IX expression and prognosis in OSCC • CA-IX expression in other HNSCCs • Relationship between CA-IX and chemoresistance or radioresistance • The relationship between CA-IX and other molecules • Role of CA-IX as therapeutic target against cancer • Conclusions

  17. Koukourakis et al 2001 • CA-IX expression (26.6%, 20 of 75) takes place mainly in tumors with low vascularization (CD-31), necrosis areas • CA-IX expression related to a poor overall response  These results were confirmed by Jonathan et al and Beasley et al

  18. Bhattacharya et al 2004 • HNSCC xenograft b. Lack of microvessels in well-differentiated areas of the xenograft related to hypoxia and positive for CA-IX  a limited use of chemotherapeutic drugs  resistance to Irinotecan therapy • Hypoxia promoted the creation of resistant cell subpopulations

  19. Chintala et al 2010 • The effect of Se-methylselenocysteine in HNSCC cell lines and xenografts b. In cells and hypoxic areas, the combination of both drugs  1. reduced HIF-1a levels 2. lowered CA-IX levels

  20. Zheng et al 2010 • Transformed an OSCC  into PYM resistant and crossresistant to paclitaxel, Adriamycin, mitomycin b. Application of CA inhibitor, acetazolamide, and CA-IX silencing with oligonucleotides  PH ↑ in resistant cells  increase of chemosensitivity to PYM

  21. Eriksen et al 2007 • CA-IX as prognostic marker in a series of 320 HNSCCs undergoing radiotherapy + nimorazole b. CA-IX is not related to any clinical and pathological, prognostic parameters

  22. Patients treated with ARCON vs. conventional surgery ± radiotherapy  the hypoxia and vascula density levels have no influence on treatment response • Jonathan et al 2006 Relationship between CA-IX and the lack of locoregional control • disappears when tumors are treated with ARCON *accelerated radiotherapy combined with carbogen and nicotinamide

  23. Koukourakis et al 2006 • Joint expression of HIF-2a and CA-IX is responsible for poor CHART results * Continuous hyperfractionated accelerated radiotherapy

  24. Introduction • CA-IX expression and prognosis in OSCC • CA-IX expression in other HNSCCs • Relationship between CA-IX and chemoresistance or radioresistance • The relationship between CA-IX and other molecules • Role of CA-IX as therapeutic target against cancer • Conclusions

  25. HIF • HIF-1a transcription is the regulating factor in cellular response to hypoxia • In the case of OSCC, HIF-1a prevents apoptosis of tumor cells • Zhu et al 2010 OSCC cell lines are cultivated with 1% O2 expression of mRNA CA-IX is regulated by HIF-1a

  26. Chintala et al 2010 • Application of Se-methylselenocysteine combined with irinotecan • HIF-1a ↓ CA-IX ↓ • Koukourakis et al • CA-IX expression  worse survival rates • HIF-2a  worse locoregional control • Joint expression provoked an additive effect  confirm relation between both markers

  27. Eckert et al 2010 HIF-1a & CA-IX • low expression of both proteins survived an average of 54.8 months • high HIF-1a and low CA-IX expression survived an average of 37.6 months; tumor-related death risk was 4.97-fold

  28. Roh et al 2009 • Statistically significant relationship between CA-IX and HIF-1a and HIF-2a • Winter et al  Not confirm a positive correlation with HIF-1a nor HIF-2a

  29. Ki-67 • Kim et al 2007 CA-IX & Ki-67 • Correlation between both • Established three patterns: (1) high risk (elevated CA-IX ⁄ Ki-67) (2) low risk (low CA-IX ⁄ Ki- 67) (3) moderate risk (one of the two is elevated)  The high-risk group was an independent prognostic factor for average survival and disease-free survival

  30. Kondo et al 2011 no relationship between Ki-67 expression and CA-IX

  31. GLUT-1 • Schutter et al 2005 CA-IX & GLUT-1 (glucose transporter-1) • CA-IX expression was not related to 1. any of the clinical, pathological, or prognostic parameters 2. the expression of GLUT-1 • Kondo et al 2011 & Jonathan et al 2006  not found relation between GLUT-1 expression and CA-IX

  32. Erythropoietin (Epo) and erythropoietin receptor (EpoR) • Winter et al 2005 • Tried to link tumor hypoxia and its main marker, CA-IX, with Hb, Epo, and EpoR • Positive correlation in CA-IX and Epo, but not EpoR • No correlation between Hb and Epo or EpoR

  33. Other molecules • Le et al 2007 significant relationship between intense CA-IX expression and hypoxia-related proteins: BNIP3L, LOX, CTGF, Ephrin A1, GAL-1

  34. Le et al 2007 Positive correlation between the expression of CA-IX and Galectin-1 and their relation with treatment outcome • Silva et al 2010 Co-expression of CA-IX and MVP (major vault protein) confers tumors a significantly lesser chance of locoregional control

  35. Gee et al 2010 • Abnormally high levels of microRNA hsa-miR-210 in 46 HNSCC patients • Statistically significant relationship between hypoxia markers such as HIF-1a, the TWIST1 gene, and CA-IX • Locoregional recurrence with a smaller average survival

  36. Schutter et al 2006 • Analyzing the relation between micro-satellite alterations and HNSCC tumor hypoxia • LOH (loss of heterozygosity) is very frequent in regions close to p53, specifically in D17S799, in patients that simultaneously showed high CA-IX expression • supporting the theory of the relationship between p53 and hypoxia

  37. Introduction • CA-IX expression and prognosis in OSCC • CA-IX expression in other HNSCCs • Relationship between CA-IX and chemoresistance or radioresistance • The relationship between CA-IX and other molecules • Role of CA-IX as therapeutic target against cancer • Conclusions

  38. CA-IX and XII are predominantly found in tumor cells • Hydrating carbon dioxide to protons and bicarbonate, these CAs contribute significantly to the extracellular acidification of solid tumors • CA-IX is overexpressed in many tumors in response to the HIF pathway

  39. Design campaigns of inhibitors against this novel, recently validated antitumor target • Obtaining compounds that specifically target the tumor-associated isoforms CA-IX and XII • Coumarin and thiocoumarins are the most important such new CAIs

  40. Lou Y et al 2011 PacchianoF et al 2011  • The most interesting CAIs reported to date are the ureido-sulfonamide and the glycosylcoumarin(low nanomolar CA-IX selective inhibitors)  which strongly inhibit the growth of both primary tumors and metastases in several animal models of breast cancer

  41. Similar animal model of breast cancer cell lines which does not express CA-IX has been used as negative control  no effects on the growth of the tumors have been evidenced after treatment with sulfonamide ⁄ coumarin CAIs

  42.  demonstrated the potential of CA-IX inhibition for designing antitumor ⁄ antimetastatic agents possessing a novel mechanism of action

  43. Zatovicova M et al 2010  • M75 is a highly specific anti-CA-IX mAbtargeting the PG domain of CA-IX used in immunohistochemical and western blot studies for evidencing CA-IX

  44. SiebelsM et al 2011  • WX-G250(Girentuximab) is another anti-CA-IX chimeric monoclonalantibody in phase III clinical trials as adjuvanttherapy for the treatmentofnon-metastasized RCC

  45. Tumor-associatedCAs are indeed almost ideal targets for designing novel and innovative anticancer drugs • Interfere with tumor acidification by a mechanism of action not yet exploited by the classical cytostatic drugs

  46. Introduction • CA-IX expression and prognosis in OSCC • CA-IX expression in other HNSCCs • Relationship between CA-IX and chemoresistance or radioresistance • The relationship between CA-IX and other molecules • Role of CA-IX as therapeutic target against cancer • Conclusions

  47. Hypoxia in solid tumors is a decisive factor for the outcome of HNSCCs • Hypoxia in solid tumors with chemoresistance and the failure of radiotherapy, both conventional and concomitant, in which CA-IX seems to play an important role

  48. Several mAbs(girentuximab, and its 124I-radiolabelled variant) targeting CA-IX  in advanced clinical trials both for a. treatment b. imaging of hypoxic tumors overexpressing this enzyme

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