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ECCLU 2011 - C. Rothermundt - Mechanisms of action in modern RCC treatment
 

ECCLU 2011 - C. Rothermundt - Mechanisms of action in modern RCC treatment

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    ECCLU 2011 - C. Rothermundt - Mechanisms of action in modern RCC treatment ECCLU 2011 - C. Rothermundt - Mechanisms of action in modern RCC treatment Presentation Transcript

    • Mechanisms of Action in Modern RCC Treatment
    • Conflict of Interest Declaration
      BAYER – Advisory Board
      GLAXOSMITHKLINE – Advisory Board
      NOVARTIS – Support for this talk
    • Renal Cell Cancer – Histological Subtypes
      BHD, Birt-Hogg-Dubé; VHL, von Hippel-Lindau.
      Linehan WM, et al. Clin Cancer Res. 2007;13:671s-9s.
    • Von Hippel-Lindau (VHL) Protein Controls the Expression of the HIF- Transcription Factors
      HIF, hypoxia-inducible factor; HRE, hypoxia-responsive element; VEGF, vascular endothelial growth factor.
      Cohen HT, et al. N Engl J Med. 2005;353:2477-90.
    • VHL Loss Is Prevalent in RCC
      The majority of clear cell RCCs lack functional VHL protein1
      This loss of function may occur via VHL gene mutations or epigenetic silencing via promoter hyper-methylation1,2
      Recent studies have found VHL inactivation in RCC (via mutation or hyper-methylation) to be quite widespread
      90% of 78 patients assessed3
      91% of 205 patients assessed4
      1. Gossage L, Eisen T. Nat Rev Clin Oncol. 2010;7:277-88.
      2. Gnarra JR, et al. Nat Genet.. 1994;7:85-90.
      3. Hutson TE, et al. J Clin Oncol. 2008;26(15S):5046.
      4. Nickerson ML, et al. Clin Cancer Res. 2008;14:4726-34.
      RCC, renal cell carcinoma.
    • VHL Loss Fuels Accumulation of HIF and Uncontrolled Angiogenesis in RCC
      PDGF, platelet-derived growth factor; PDGFR, PDGF receptor; VEGFR, VEGF receptor.
      Rini BI. Cancer. 2009;115:2306-2312.
    • Anti-VEGF Treatment
    • VEGF and VEGFR Blockade Inhibit Angiogenesis and Tumour Growth in RCC
      Rini BI. Clin Cancer Res. 2007;13:1098-106.
      Ellis LM, Hicklin DJ. Nat Rev Cancer. 2008;8:579-91.
    • Response and Duration of Response to Anti-VEGF or Anti-VEGFR Treatment
      CR, complete response; ORR, objective response rate, PD, progressive disease; PFS, progression-free survival; PR, partial response.
      1. Motzer RJ, et al. N Engl J Med. 2007;356:115-24.
      2. Escudier B, et al. Lancet. 2007;370:2103-2111.
      3. Sternberg C, et al. J Clin Oncol. 2010;28:1061-1068.
    • Adaptive resistance:VEGF-targeted agents fail to produce enduring clinical responses in most patients
      Intrinsic resistance:No predictive biomarkers available to date
      Bergers G, Hanahan D. Nat Rev Cancer. 2008;8:592-603.
      Resistance to VEGF-targeted Therapy Is a Key Clinical Issue
    • VEGFR-TKI Therapy Activates Alternate Pro­angiogenic Pathways
      Early Phase: Response to VEGF-targeted therapy
      Late Phase: Angiogenic escape of VEGF blockade
      Cancer cells
      VEGF
      Cancer cells
      VEGF
      FGF, IL-8,
      others
      No Angiogenesis
      Reactivation of Angiogenesis
      Hypoxia
      Endothelial cells
      Endothelial cells
      Inhibition of VEGF signaling transiently stops tumour growth and decreases vascularity
      Activation of other pro-angiogenic factors leads to tumour progression
      FGF, fibroblast growth factor; IL, interleukin; TKI, tyrosine kinase inhibitor.
      Figure revised from: Casanovas O, et al.
      Cancer Cell. 2005;8:299-309.
    • Anti-VEGFR2 Therapy Induces an Invasive Phenotype
      Control (end-stage)
      Anti-VEGFR2 1 week
      Anti-VEGFR2 4 weeks
      H&E
      Anti-T antigen
      Anti-CD31
      H&E, hematoxylin and eosin.
      Paez-Ribes M, et al. Cancer Cell. 2009;15:220-31.
    • VEGFR Inhibition Triggers Upregulation of FGF and Other Angiogenic Factors
      In a mouse model of pancreatic islet carcinogenesis (RIP-Tag2):
      Resistance to VEGFR2 antibody was accompanied by up-regulation of mRNA expression for several pro-angiogenic factors, including FGF1, FGF2, FGF7, and Ang-1, in tumour and/or stromal cells
      2.5
      2.0
      1.5
      Fold Change in Expressionin VEGFR2-blocked vs Control
      1.0
      0.5
      0
      FGF1
      FGF2
      FGF7
      VEGF
      EphA2
      FGFR1
      FGFR2
      VEGFR1
      VEGFR2
      Angiop.1
      Angiop.2
      EphrinA1
      Casanovas O, et al. Cancer Cell. 2005;8:299-309.
    • Additional Possible Mechanisms of Resistance to VEGFR-TKI Therapy
      Hypoxia HIF1-a circulating VEGF and PDGF 
      Placental growth factor (PlGF)
      Inter-molecular crosstalk between FLT1 and FLK1
      Up-regulation of the expression of VEGF-A, FGF2, PDGFB, MMPs
      Up-regulation of pro-angiogenic stromal cells
      Tumour-associated fibroblasts (TAFs)
      Bone marrow-derived cells
      Vascular progenitors and pro-angiogenic monocytic cells, TIE2+ monocytes, VEGFR-1+ hemangiocytes, CD11b+ myeloid cells
      Inadequate target inhibition
      Azam F, et al. Eur J Cancer. 2010;46:1323-1332
    • Increased Secretion of IL-8 Linked to Sunitinib Resistance in RCC
      786-O Xenograft
      IL-8 Level in Plasma From786-O Xenograft Mice (Day 68)
      0.8
      *
      3.0
      Sensitive
      Resistant
      2.5
      0.6
      2.0
      (n = 15)
      0.4
      1.5
      Tumor Growth Ratio
      IL-8(pg/mL/mm3 tumor)
      1.0
      0.2
      (n = 3)**
      0.5
      0
      0
      33
      36
      67
      40
      43
      46
      48
      50
      53
      55
      57
      60
      62
      64
      Control
      Sensitive
      Resisitant
      Time After Tumor Inoculation (d)
      Huang D, Ding Y, Zhou M, et al. Cancer Res. 2010;70:1063-1071.
    • IL-8 Expression Is Increased in Patients With Intrinsic Resistance to Sunitinib
      IL-8 scoring
      Negative
      Weakly positive
      Strongly positive
      Sunitinib sensitive
      Sunitinib refractory
      Huang D, Ding Y, Zhou M, et al. Cancer Res. 2010;70:1063-1071.
    • Re-challenge With Anti-VEGF Treatment
      Sunitinib in bevacizumab-refractory patients1
      Axitinib in sorafenib-refractory patients2
      Sunitinib re-challenge after previous treatment with sunitinib3
      1. Rini BI, et al. J Clin Oncol. 2008;26:3743-3748.
      2. Rini BI, et al. J Clin Oncol. 2009;27:4462-4468.
      3. Zama IN, et al. Cancer. 2010;116:5400-5406.
    • Summary: VEGF Inhibitors
      Loss of functional VHL and over-expression of HIF drive uncontrolled angiogenesis in RCC
      VEGF-targeted agents inhibit angiogenesis and have become the standard-of-care first-line treatment in mRCC
      Durable responses to VEGF-targeted agents are rare, and resistance can arise via multiple mechanisms
    • mTOR Inhibition
    • mTOR Inhibition Blocks HIF-1 Production and Slows Tumour Growth in RCC
      Everolimus
      Temsirolimus
      mTOR, mammalian target of rapamycin.
      Rini BI. J Clin Oncol. 2009;27:3225-34.
      Morgensztern D, McLeod HL. Anticancer Drugs. 2005;16:797-803.
    • mTOR Blockade Affords Broad Inhibition of Tumour Vasculature
      In a mouse model of melanoma (B16/BL6):
      Everolimus reduces VEGF in tumour and plasma, while the VEGFR-TKI vatalanib (PTK787) only reduces plasma VEGF
      Everolimus has a more profound effect on mature blood vessels (by SMA staining of smooth muscle cells)
      SMA, smooth muscle antibody.
      Lane HA, et al. Clin Cancer Res. 2009;15:1612-22.
    • Temsirolimus Improves OS in Patients With Poor Prognosis mRCC
      n = 626; all histologies
      1.00
      Temsirolimus: median OS 10.9 months
      Interferon: median OS 7.3 months
      0.75
      Temsirolimus
      0.50
      Probability of Survival
      Combination
      Interferon
      0.25
      0.00
      0
      5
      10
      15
      20
      25
      30
      Months
      mRCC, metastatic RCC; OS, overall survival.
      Hudes G, et al. N Engl J Med. 2007;356:2271-81.
    • Everolimus Shows Clinical Efficacy in VEGFR-TKI-refractory mRCC
      n = 416, clear cell histology
      100
      Everolimus: median PFS 4.90 months
      Placebo: median PFS 1.87 months
      80
      HR: 0.33
      (95% CI: 0.25, 0.43)
      Log rank P < .001
      60
      Probability, %
      40
      20
      0
      0
      2
      4
      6
      8
      10
      12
      14
      Time, months
      CI, confidence interval; HR, hazard ratio.
      Motzer RJ et al. Cancer. 2010;116:4256-65.
    • PI3K/Akt Activation May Drive Resistance to mTORC1 inhibitors
      Everolimus
      Temsirolimus
      Figure adapted from:
      Rini BI, Atkins MB. Lancet Oncol. 2009;10:992-1000.
    • Novel Strategies for Targeting PI3K/Akt/mTOR Signaling in RCC are emerging
      Dual PI3K/mTOR inhibitor BEZ235
      786-O
      2500
      NVP-BEZ235
      BEZ235
      Rapamycin
      2000
      V
      ehicle
      1500
      Volume (mm3)
      1000
      500
      0
      0
      1
      3
      5
      7
      9
      11
      13
      15
      17
      19
      21
      Days
      BEZ235 treatment resulted in growth arrest, compared to slight tumor regression with rapamycin
      Figure adapted from: Rini BI, Atkins MB. Lancet Oncol. 2009;10:992-1000.
      Cho DC, et al. Clin Cancer Res. 2010;16:3628-38.
    • mTOR Inhibition Activates MEK/ERK SignalingMEK and EGFR inhibitors may overcome mTOR resistance
      Wang X, et al. Cancer Biol Ther. 2008;7:1952-8.
    • Summary: mTOR Inhibitors
      Inhibition of mTOR overcomes resistance to VEGF-targeted agents in mRCC
      Temsirolimus is the standard of care in patients with poor prognosis mRCC and everolimus is the standard of care in patients with mRCC who have failed initial VEGFR-TKI therapy
      mTORC2 complex is neither inhibited by temsirolimus nore everolimus
      mTORC1 inhibition may cause compensatory activation of PI3K and AKT
    • Other Investigational Targets in RCC
    • FGFR/FGF Signaling Is Dysregulated in Cancer
      Dysregulated expression of FGFs or FGFRs due to genetic or epigenetic changes1
      FGF signaling plays a prominent role in angiogenesis1
      Highly vascularised tumours, e.g. RCC, often contain high levels of FGFs and FGFRs after treatment with VEGF pathway inhibitors2
      FGFR, FGF receptor.
      1. Korc M, Friesel RE. Curr Cancer Drug Targets. 2009;9:639-51.
      2. Presta M, et al. Cytokine Growth Factor Rev. 2005;16:159-78.
    • Dovitinib (TKI258) Inhibits FGFR and Other TKIs
      Inhibits the tyrosine kinase activity1 of
      FGFR, VEGFR
      PDGFR, c-KIT, FLT-3, CSF1R
      Nanomolar IC50 values1
      Exhibits direct anti-tumour and anti-angiogenic activity2
      Oral dosing2
      Clinical trials ongoing in renal, breast, and urothelial cell cancers and in multiple myeloma
      IC50, half maximal inhibitory concentration.
      Lopes de Menezes DE, et al. Clin Cancer Res. 2005;11:5281-91.
      Renhowe PA, et al. J Med Chem. 2009;52:278-92.
    • Targeting HGF/c-Met Signaling in Papillary RCC
      Hereditary and sporadic papillary RCCs show activating mutations in the c-Met receptor tyrosine kinase
      HGF/c-Met signaling is also implicated in angiogenesis
      Several c-Met inhibitors are now in clinical trials, including:
      Foretinib
      ARQ 197
      HGF, hepatocyte growth factor.
      Maulik G, et al. Cytokine Growth Factor Rev. 2002;13:41-59.
      Figure adapted from Sekulic A et al. Mayo Clin Proc. 2008;83:825-46.
    • c-Met as a Target in Clear Cell RCC
      Analysis of c-Met protein expression in 317 RCC tumour specimens
      c-Met is expressed in all RCCs, including those of clear cell histology
      Expression is highest in tumours with papillary and sarcomatoid histology
      High c-Met expression correlates with higher tumour grade (P = .0019) and clinical stage (P = .0208)
      High c-Met expression is an independent predictor of poor OS (P = .017) in RCC, including the clear cell subtype
      Gibney G, et al. J Clin Oncol. 2011;29(7 suppl):360.
    • CTLA-4 and PD-1 Blockade May Prolong T-cell Activation in Multiple Tumour Types
      Ipilimumab, an anti-CTLA-4 monoclonal antibody, was recently approved by the US Food and Drug Administration for use in patients with metastatic melanoma2
      1. Kandalaft LE, et al. J Clin Oncol 29:925-933.
      2. “Ipilimumab”, http://www.fda.gov/AboutFDA/CentersOffices/CDER/ucm248478.htm.
    • Anti-CTLA-4 mAbs Show Preliminary Efficacy in mRCC
      Phase I dose-escalation study of tremelimumab in combination with sunitinib in mRCC1
      21 patients enrolled; 9 achieved a PR
      Phase II trial of ipilimumab monotherapy in patients with mRCC2
      61 patients enrolled; 6 achieved a PR
      33% of patients experienced grade 3/4 autoimmune-mediated toxicity
      Significant association between autoimmune events and anti-tumour activity
      30% response rate in 20 patients with autoimmune toxicity
      0% response rate in 41 patients with no autoimmune toxicity
      P = .0007
      1. Rini BI, et al. Cancer. 2011;117:758-67.
      2. Yang JC, et al. J Immunother. 2007;30:825-30.
    • MDX-1106, a Fully Human Anti-PD-1 mAb, Affords Tumour Regression in a Patient With mRCC
      1 patient with mRCC in a phase I dose-escalation trial of MDX-1106 in patients with refractory solid tumours
      Previously treated with sunitinib, sorafenib, and an experimental histone deacetylase inhibitor
      PR for 16+ months
      Regression of Metastases in Mediastinal Lymph Nodes by Contrast-enhanced CT Scan in a Patient With mRCC After Repeat Dosing With MDX-1106 at 10 mg/kg.
      CT, computed tomography.
      Brahmer JR, et al. J Clin Oncol. 2010;28:3167-75.
    • Conclusions
      Novel therapeutic targets currently under investigation may provide treatment options for patients who progress after VEGF-targeted treatment and mTOR inhibitors
      Predictive markers are needed for treatment selection
      Definition of resistance by RECIST criteria has limitations
      Functional imaging needs validation and has to become widely available
      Dose escalation, drug combinations, dual pathway inhibition and sequencing of treatments are therapeutic strategies
      RECIST, Response Evaluation Criteria In Solid Tumors.