Malignant pleural effusion _MPE_ Pathophysiology of malignant by dandanhuanghuang

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									Malignant pleural
effusion (MPE)
Pathophysiology of         Georgios T, Stathopoulos MD PhD
                           Assistant Professor
malignant pleural          Laboratory for Molecular Respiratory Carcinogenesis
                           Department of Physiology
effusion: promises         School of Medicine
                           University of Patras
for the future             Rio
                           Greece
                           gstathop@upatras.gr
                           www.molcellbiol-upatras.net




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                         Lee YC, Wilkosz S. Malignant pleural effusions:
Relevant reviews         fixing the leaky faucet. Am J Respir Crit Care Med
                         2008;178:3-5

                         Mishra EK, Davies RJ. Advances in the
                         investigation and treatment of pleural effusions.
                         Expert Rev Respir Med 2010;4:123-33

                         Stathopoulos GT. Translational advances in
                         pleural malignancies. Respirology 2011;16:53‐63

                         Kalomenidis I. Beyond talc pleurodesis: do we
                         really need new methods? Respirology
                         2011;16:1020-2




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MPE
disease burden
•   15 % of all cancer pts
•   500-700/mio/yr
•   > 2 mio/yr                                           Antunes G et al. Thorax 2003;58:ii29-38

•   > 70 % ADCA (lung, breast,
    GI, GU)
•   rest: lymphoma
•   median survival 3 mos
•   IASLC 2009 T4 → M1
•   reduces quality of life
    (dyspnea, pain from
    disease & treatment)
•   obviates surgery
•   interferes with non-
    surgical treatment
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MPE
treatment
                             Burgers JA, et al. Eur Respir J 2008;32:1321-7
• Pts too sick: nada,        100 patients with MPE
  aspiration                 25 unfit
                             27 recurred within 17 days
• Pts fit: chest tubes,
                             14 patients with successful pleurodesis died within
  pleurodesis,               13-174 days
  thoracoscopy,              only 34 (1/3) saw benefit
  pleuroperitoneal
  shunt, chemotherapy
• NO DIFFERENCE in
  outcome
• Only palliative role for
  current “treatments”


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Pleural fluid
turnover
Production
- parietal pleural capillary
  filtration
- mesothelial barrier
  trespassing
Absorption
- parietal pleural
  lymphatics (stomata)
- electrolyte-coupled liquid
  outflow
- Mesothelial transcytosis
                                  Flux (µl/h/kg)
- x 30 reserve                    1: 150-200           4: 70
Flux 0.5 ml/h                     2: 100               5: 20
Volume 0.26±.1 ml/kg              3: 70 (protein)              Zochi L. Eur Respir J 2002;20:1545-58

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MPE
pathophysiology
Enhanced production
- vascular hyper-
  permeability
- mesothelial hyper-
  permeability                           + +               x
Decreased absorption
- lymphatic block
- increased interstitial
  pressure                                         x
                                                       Zochi L. Eur Respir J 2002;20:1545-58



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Reductionist
MPE view
- Proliferating
  intrapleural tumor
  mass mechanically
  obliterates pleural
  cavity (PC) outflow
  overwhelming
  reserve
- Profound impact on
  contemporary
  therapeutics
- Eliminate MPE/PC
                                                    Antunes G et al. Thorax 2003;58:ii29-ii38



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Heterotypic MPE
biology
- Intrapleural tumor
  cells in close
  signaling interplay
  with host cells
  leading to enhanced
  PF production
- No impact on
  management
- Suppress MPE
  production; use
  MPE to monitor
  response to Tx
                                                    Hanahan D, Weinberg RA. Cell 2011;144:646-74
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Reductionist                                   Heterotypic
advances                                       advances
- Pleurodesis agents                           - Biologic
- Pleural catheters                              understanding of
                                                 pleural oncogenesis
- Local Tx
                                                 and paths to MPE
- Imaging                                        development
- Pleural stereology-                          - Identification of
  morphometry                                    molecular targets
- Biomarkers                                   - Preclinical
                                                 therapeutics
                                               - Oncogene-host
                                                 interactions


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Pleurodesis
                           Janssen JP et al. Safety of pleurodesis with talc poudrage in
-   Talc safety            malignant pleural effusion: a prospective cohort study. Lancet
                           2007;369:1535–9
-   Silver nitrate         Paschoalini S et al. Prospective randomized trial of silver nitrate
                           vs talc slurry in pleurodesis for symptomatic malignant pleural
-   Povidone iodide        effusions. Chest 2005;128:684–9

-   Lipoteichoic acid-T    Neto et al. Efficacy and safety of iodopovidone pleurodesis in
                           malignant pleural effusions. Respirology 2010;15:115–18

-   OK-432                 Rahman NM et al. Use of lipoteichoic acid-T for pleurodesis in
                           malignant pleural effusion: a phase I toxicity and dose-escalation
-   Transforming growth    study. Lancet Oncol 2008;9:946–52

    factor (TGF)-β         Yoshida K et al. Randomized phase II trial of three intrapleural
                           therapy regimens for the management of malignant pleural
                           effusion in previously untreated non-small cell lung cancer:
                           JCOG 9515. Lung Cancer 2007;58:362–8

                           Light RW et al. A single intrapleural injection of transforming
                           growth factor-beta(2) produces an excellent pleurodesis in
                           rabbits. Am J Respir Crit Care Med 2000;162:98–104




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Other local Tx
                           Tremblay A et al. Use of tunnelled catheters for malignant pleural
- Pleural catheters        effusions in patients fit for pleurodesis. Eur Respir J
                           2007;30:759-62
- Gene transfer            Gauvrit A et al. Measles virus induces oncolysis of mesothelioma
                           cells and allows dendritic cells to cross-prime tumor-specific CD8
- Local chemoTx            response. Cancer Res 2008;68:4882–92

                           Watanabe M et al. AAVrh.10-mediated genetic delivery of
                           bevacizumab to the pleura to provide local anti-VEGF to
                           suppress growth of metastatic lung tumors. Gene Ther
                           2010;17:1042–51

                           Wang X et al. A phase I clinical and pharmacokinetic study of
                           paclitaxel liposome infused in non-small cell lung cancer patients
                           with malignant pleural effusions. Eur J Cancer 2010;46:1474–80

                           Jones DR et al. Phase I trial of intrapleural docetaxel
                           administered through an implantable catheter in subjects with a
                           malignant pleural effusion. J Thorac Oncol 2010;5:75–81




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                           Qureshi NR et al. Thoracic ultrasound in the diagnosis of
                           malignant pleural effusion. Thorax 2009;64:139–43
Morphologic                Wrightson JM et al. Risk reduction in pleural procedures:

Imaging                    sonography, simulation and supervision. Curr Opin Pulm Med
                           2010;16:340–50


Thoracic US                Fasola G et al. Low-dose computed tomography screening for
                           lung cancer and pleural mesothelioma in an asbestos-exposed
                           population: baseline results of a prospective, nonrandomized
- Diagnosis                feasibility trial—an Alpe-adria Thoracic Oncology Multidisciplinary
                           Group Study (ATOM 002). Oncologist 2007;12:1215–24
- Safety of                Kim KW et al. The utility of multi-detector computed tomography
                           in the diagnosis of malignant pleural effusion in the patients with
  interventions            ovarian cancer. Eur J Radiol 2010;75:230–5

Thoracic CT                Metintas M et al. Medical thoracoscopy vs CT scan-guided
                           Abrams pleural needle biopsy for diagnosis of patients with
                           pleural effusions: a randomized, controlled trial. Chest
- Early Dx                 2010;137:1362–8

- Less-invasive Dx         Liu F et al. Assessment of therapy responses and prediction of
                           survival in malignant pleural mesothelioma through computer-
                           aided volumetric measurement on computed tomography scans.
Stereology                 J Thorac Oncol 2010;5:879-84

- Accurate                 Hsia CC et al, ATS/ERS Joint Task Force on Quantitative
                           Assessment of Lung Structure. An official research policy
  assessment of            statement of the American Thoracic Society/European
                           Respiratory Society: standards for quantitative assessment of
  pleural tumor burden     lung structure. Am J Respir Crit Care Med 2010;181:394-418


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Metabolic
Imaging
PET/CT
- Diagnosis
- Staging
- Prediction of
  response to
  treatment



           Francis RJ et al. Early prediction of
     response to chemotherapy and survival in
       malignant pleural mesothelioma using a
          novel semiautomated 3-dimensional
     volume-based analysis of serial 18F-FDG
     PET scans. J Nucl Med 2007;48:1449–58

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Biomarkers
Early detection
Non-invasive Dx
Definitive Dx
- SMRP
- OPN
- CD146
- Calretinin
                           Saliba AE et al. Microfluidic sorting and multimodal typing of cancer cells in self-
- Gene X                   assembled magnetic arrays. Proc Natl Acad Sci USA 2010;107:14524–9

- TSP2
- Microfluidic multi-
  modality typing
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Mesothelial
oncogenesis
Combined loss of tumor
suppressors
-neurofibromatosis 2 (NF2
encoding Merlin)
-tumor-related protein 53
(Trp53)
-p16/INK4A/Arf
…is sufficient to cause
MPM in mice
•gene therapy to restore
endogenous tumor
suppressors in MPM
•NF2 biomarker of anti-
                                 Jongsma J et al. A conditional mouse model for malignant
mTOR response                    mesothelioma. Cancer Cell 2008;13:261–71


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The VEGF
signaling story
- Present in MPE
- Elaborated by tumor cells
- VEGFR expressed by
  endothelium/mesothelium
- Enhances vascular
  permeability and
  angiogenesis
- Required for MPE
  formation
- Beneficial effects against
  non-squamous NSCLC
- Ongoing studies in
  MPM/MPE (NCT00402896,
  NCT00343291,                 Zebrowski BK et al. Clin Cancer Res 1999;5:3364-8
  NCT00250978,                 Thickett DR et al. Thorax 1999;54:707-10
                               Yano S et al. Am J Pathol 2000;57:1893-903
  NCT00351039)
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A requirement for
expression of a
distinct gene set
-   VEGF
-   IL-6
-   TNF
-   CCL2
-   SPP1
-   Angs
-   Comparative genomics:
    Cxcl16, Cxcr7, Fgf11,
    Il2rg, Mmp9, Mmp11,
    Tnfrsf9???

                                Yeh HH et al. Oncogene 2006;25:4300-9
                                Stathopoulos GT et al. Cancer Res 2007;67:9825-34
                                Stathopoulos GT et al. J Natl Cancer Inst 2008;100:1464-76
                                Psallidas et al. Submitted
                                Moschos C et al. Neoplasia 2009;11:298-304

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A MPE-associated
transcriptional
signature
- Stat3
- NF-κΒ
- Non-canonical NF-κΒ                                                    RelB
                                                          RelA
  activity appears to be
  important




                                           MCF7
- …




                                           B16F10   DAPI
                                                    RelA/RelB
                                                    merge

                               Stathopoulos GT et al. Am J Respir Cell Mol Biol 2006;34:142-50
                               Yeh HH et al. Oncogene 2006;25:4300-9
                               Stathopoulos GT et al. Cancer Res 2007;67:9825-34
                               Spella M et al. Work in progress.

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A defined set of
genetic alterations?
-   Kras
-   Trp53
                          Wu SG et al. Eur Respir J 2008;32:924–30
-   PIK3CA
-   EGFR
-   …




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                                          A            150                                                         C                            1.5

                                                                       **                                                                                                               ***
                                                                                                                                                                                                    *
A cellular host                                        100                                                                                       1




                                  mast cells (x 103)




                                                                                                                           mast cells (/hpf)
                                                                               **
response profile                                        50                                                                                      0.5


                                                         0                                                                                            0
-   MDSCs                                                     B16F10   LLC    MC38                                                                           B16F10                     LLC      MC38
                              MPE competence                    -       +      +                                     MPE competence                                           -          +          +
-   Mononuclear cells
                                        B                                                                         D
-   Eosinophils
-   Mast cells
                                                        LLC            MC38                                       B16F10                                  LLC                                 MC38
-   TANs
                                                                                                                       wt (n = 7)                                             cKitWsh/Wsh (n = 7)
-   …
                                                                                     A                      2                  ***
                                                                                                                                                           B                  1500




                                                                                     ∆ body mass (gr)
                                                                                                                                                                              1000




                                                                                                                                                            MPE volume (µl)
                                                                                                            0


                                                                                                            -2                                                                    500
                                                                                                                                                                                                     ***

                                                                                                            -4                                                                     0

                                                                                     C                                                                      D
                                                                                                                 P > .05
                                                                                                                                                                      wt                      cKitWsh/Wsh




                                                                                     pleural tumor number
                                                                                                            20



                                                                                                            10

                            Kairi CA et al. Manuscript
                            in draft.                                                                        0
                                                                                                                  parietal                     visceral

30/11/2011              20ο ΠΣΝΘ - Σταθόπουλος ΓΘ                                                                                                                                                       20
A host inflammatory
response
- wt tumor cells
- NF-κΒ reporter mice
- Host NF-κΒ activation
  specifically in MPE-
  bearing hosts




                                     Spella M et al. Work in progress.




30/11/2011                20ο ΠΣΝΘ - Σταθόπουλος ΓΘ                      21
A heterotypic path
to MPE
- Tumor homing to pleura
- Expression of distinct
  gene set driven by
  tumor-specific mutations
  and transcriptional
  activity
- Direct provocation of
  vascular leak
- Chemorecruitment of
  host cells
- Elaboration of
  vasoactive mediators by
  host cells


30/11/2011                   20ο ΠΣΝΘ - Σταθόπουλος ΓΘ   22
Biologic Tx
- Bevazicumab
- Etanercept                    x
- anti-CCL2/12

                                             x   x




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Small molecule
inhibitors
- TKIs
- NBPs
   RAS blockers
   Differential sensitivity of
   various mouse and human
   tumors dependent on
   mutation status




                                      Stathopoulos GT et al. Am J Respir Crit Care Med 2008;178:50-9



30/11/2011                       20ο ΠΣΝΘ - Σταθόπουλος ΓΘ                                             24
Future research
improvements
- Clinical trial design      - Pharmacologic treatment of MPE
- Separate study of MPE        reducing the need for interventions and
- Further separation of        hospitalization
  primary (MPM)-             - Improved QOL, survival
  secondary MPE              - Targeted therapies based on
- User-independent             genome/phenome
  assessment of pleural
  tumor progression
- Cooperative efforts
- Tissue/data banks




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Acknowledgements

                                     T Agalioti        A Moustaki
                                     A Giannou         ZM Prijovic
                                     A Marazioti       M Spella

                                     TS Blackwell      VV Polosukhin
                                     FE Yull           TP Sherrill
                                     B Fingleton       LA Gleaves
                                     W Han             FB McMahon
                                     R Zaynagetdinov   KB Lane

                                     I Kalomenidis     C Roussos
                                     C Moschos         N Kollintza
                                     I Psallidas       S Magkouta
                                     SG Zakynthinos    SP Karabela
                                     CA Kairi          K Doris



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