targeting other receptors in net´s cells...
TRANSCRIPT
Targeting other receptors in NET´s cells surface
Dr Angela Lamarca
Research Fellow; HPB and NET Department of Medical Oncology
ENETS Centre of Excellence
The ChrisEe NHS FoundaEon Trust Manchester, UK
The Christie NHS Foundation Trust
• None to declare
Conflict of Interest
X Symposium GETNE Madrid, Oct 2014
The Christie NHS Foundation Trust
We are living a transition era in NETs
X Symposium GETNE Madrid, Oct 2014
“Classic” chemotherapy Targeted therapies
Hanahan et al, Cell, Vol. 100, 57–70, 2000
The Christie NHS Foundation Trust
What do the targeted therapies target?
X Symposium GETNE Madrid, Oct 2014
Joyce et al, Cancer Cell, 2005; DOI 10.1016/j.ccr.2005.05.024
The Christie NHS Foundation Trust
• Tumoural cells • Membrane receptors • Intracellular pathways
• Peritumoural stroma
• Neoangiogenesis
• Inmune system
What do the targeted therapies target?
X Symposium GETNE Madrid, Oct 2014
Hanahan et al, Cell, Vol. 100, 57–70, 2000
The Christie NHS Foundation Trust
• Somatostatin analogues: SSTR analogues
Targeting the NET cell: current status
X Symposium GETNE Madrid, Oct 2014
Octreotide (PROMID)
Lanreotide (Clarinet)
O Abdel-Rahman et al, in press
The Christie NHS Foundation Trust
• Intracellular pathways
Targeting the NET cell: current status
X Symposium GETNE Madrid, Oct 2014
Everolimus (mTOR)
Sunitinib (Angiogenesis)
A Lamarca et al, in press
The Christie NHS Foundation Trust
Targeting the NET cell
X Symposium GETNE Madrid, Oct 2014
• New targets in the NET cell surface
The Christie NHS Foundation Trust
Potential new cell surface targets
X Symposium GETNE Madrid, Oct 2014 Rindi er al, Nature Reviews 2011.
The Christie NHS Foundation Trust
• VEGFR • PDGFR • EGFR • cKIT • c-MET • IGFR-1 • Wnt
• TGFβ-R • FGFR • Notch • SSTR • RET • Her-2 • Hormone receptors (E/P)
Targeting the NET cell surface
X Symposium GETNE Madrid, Oct 2014
The Christie NHS Foundation Trust
• VEGFR • PDGFR • EGFR • cKIT • c-MET • IGFR-1 • Wnt
• TGFβ-R • FGFR • Notch • SSTR • RET • Her-2 • Hormone receptors (E/P)
Targeting the NET cell surface
X Symposium GETNE Madrid, Oct 2014
The Christie NHS Foundation Trust
• Trastuzumab (mAb)
• Lapatinib (TKI)
• HER2 overexpression
• Breast cancer • Gastric cancer
X Symposium GETNE Madrid, Oct 2014
Lapa tinib
Trastuzumab
Targeting HER2
Expert Rev Anticancer Ther, 2007
The Christie NHS Foundation Trust X Symposium GETNE Madrid, Oct 2014
HER2 and Hormone receptors
• 77 GEP-NETs
• PR 2+: good prognosis (early stage) • Other series higher rate of Her2 expression (15-29%) • No trials
Arnason et al.Neuroendocrinology;2011,10;93(4):249-58. Bowen et al, J Gastrointestinal Surg 2010
All pts
The Christie NHS Foundation Trust
• VEGFR • PDGFR • EGFR • cKIT • c-MET • IGFR-1 • Wnt
• TGFβ-R • FGFR • Notch • SSTR • RET • Her-2 • Hormone receptors (E/P)
Targeting the NET cell surface
X Symposium GETNE Madrid, Oct 2014
The Christie NHS Foundation Trust
cKIT
X Symposium GETNE Madrid, Oct 2014
Metastases and cell proliferation
Imatinib Oral TKI (cKIT,
PDGFR)
GIST
High mutation rate of cKIT or PDGFRA
Vidwans et al, http://therapy.collabrx.com/
The Christie NHS Foundation Trust
• Encouranging results from cell lines: cytotoxic effect
• Failed phase II trial: 27 pts
Basic research Phase II trial
X Symposium GETNE Madrid, Oct 2014 Yao et al; Clin Cancer Res 2007;13:234-240.
• Small bowel NETs • Median PFS 24 w • RR 4% (primary end-point) • IHC analyses for abl, kit,
PDGF, and PDGFR did not predict outcome.
• Bronchial carcinoid cell line NCI-H727 and the human pNET cell line BON-1
The Christie NHS Foundation Trust
• 20-40% overexpression of cKIT in IHC • Mostly high grade NETs • No mutations cKIT
• 70% overexpression PDGFR • No mutations PGFRA
• Other TK related expression
cKIT in NETs
X Symposium GETNE Madrid, Oct 2014
Perkins et al, J Natl Compr Canc Netw. 2014 June ; 12(6): 847–852.; Kostoula et al, DOI: 10.3892/or.13.4.643; Akintola-Ogunremi O et al; Am J Surg Pathol. 2003 Dec;27(12):1551-8; Ishikubo T, Jpn J Clin Oncol. 2006 Aug;36(8):494-8
The Christie NHS Foundation Trust
• VEGFR • PDGFR • EGFR • cKIT • c-MET • IGFR-1 • Wnt
• TGFβ-R • FGFR • Notch • SSTR • RET • Her-2 • Hormone receptors (E/P)
Targeting the NET cell surface
X Symposium GETNE Madrid, Oct 2014
The Christie NHS Foundation Trust
EGFR
X Symposium GETNE Madrid, Oct 2014
TKI: Gefitinib, Erlotinib mAb: Cetuximab, Panitumumab
Krasinskas - Pathology research international, 2011 Hopfner et al; British Journal of Cancer (2003) 89(9), 1766 – 1775
Insulinoma
pNET
Small Bowel
EGFR mutation (lung)
Kras WT (colorectal)
The Christie NHS Foundation Trust
EGFR: Gefitinib
X Symposium GETNE Madrid, Oct 2014
Phase II trial Eligibility criteria: PS ≤ 2 2 cohorts (96 pts): pNETs (39) and small bowel (57) Gefitinib 250 mg od End point: PFS rate at 6 months
PFS 6m: 31% (pNETs) vs 61% (small bowel) Grade ¾: infrequent: fatigue (6%), diarrhoea (5%) and
rash (3%) Rare partial responses: 3 pts
Hobday et al, ASCO 2006 Bowen et al, J Gastrointestinal Surg, 2010 Gibert et al, NEJM 2005
No mutations described Expression: 13-15%
The Christie NHS Foundation Trust
The pattern…
X Symposium GETNE Madrid, Oct 2014
FAILURE
The Christie NHS Foundation Trust
• VEGFR • PDGFR • EGFR • cKIT • c-MET • IGFR-1 • Wnt
• TGFβ-R • FGFR • Notch • SSTR • RET • Her-2 • Hormone receptors (E/P)
Targeting the NET cell surface
X Symposium GETNE Madrid, Oct 2014
The Christie NHS Foundation Trust
• VEGFR • PDGFR • EGFR • cKIT • c-MET • IGFR-1 • Wnt
• TGFβ-R • FGFR • Notch • SSTR • RET • Her-2 • Hormone receptors (E/P)
Targeting the NET cell surface
X Symposium GETNE Madrid, Oct 2014
The Christie NHS Foundation Trust
• Selected population vs Unselected population
• Biomarkers interpretation across different malignancies
• Trials end-points: adjusted to the scenario
What are we doing “wrong”?
X Symposium GETNE Madrid, Oct 2014
The Christie NHS Foundation Trust
• VEGFR • PDGFR • EGFR • cKIT • c-MET • IGFR-1 • Wnt
• TGFβ-R • FGFR • Notch • SSTR • RET • Her-2 • Hormone receptors (E/P)
Targeting the NET cell surface: new targets to explore
X Symposium GETNE Madrid, Oct 2014
The Christie NHS Foundation Trust
cMET
X Symposium GETNE Madrid, Oct 2014
Journal of Clinical Oncology, Vol 29, No 36 (December 20), 2011: pp 4837-4838
The Christie NHS Foundation Trust
• Rip-Tag2 mice model • Implication of cMET expression when VEGF inhibited
• Increase rate of N+ • cMET hyperactivation
• Reduction in lymph node expression with inhibition of cMET
cMET
X Symposium GETNE Madrid, Oct 2014
Sennino et al, Cancer Res. 2013 June; doi:10.1158/0008-5472.CAN-12-2160.
The Christie NHS Foundation Trust
cMET in lung NETs
X Symposium GETNE Madrid, Oct 2014
Voortman et al, Curr Phar Des 2013.
• Low mutation rate: 8.3% • Expression rate 65%
Typical lung NET (n=38)
Atypical lung NET (n=6)
SCLC (n=34)
Large Cell NET (n=11)
The Christie NHS Foundation Trust
• VEGFR • PDGFR • EGFR • cKIT • c-MET • IGFR-1 • Wnt
• TGFβ-R • FGFR • Notch • SSTR • RET • Her-2 • Hormone receptors (E/P)
Targeting the NET cell surface: new targets to explore
X Symposium GETNE Madrid, Oct 2014
The Christie NHS Foundation Trust
Wnt
X Symposium GETNE Madrid, Oct 2014
• Activation • APC mut • βCatenin mut • Wnt inhibitors
methylation • Others
pathways components overespression
Nibaldo, DOI: 10.5772/54606
The Christie NHS Foundation Trust
• Tissue (n=20) • βcatenin nuclear expression: 25% • βcatenin mutations • APC mutations
• Cell lines (BON) • Wnt inhibitors methylation (SFRP-1)
• New target?
Wnt
X Symposium GETNE Madrid, Oct 2014 Kim, Carcinogenesis 2013
The Christie NHS Foundation Trust
• VEGFR • PDGFR • EGFR • cKIT • c-MET • IGFR-1 • Wnt
• TGFβ-R • FGFR • Notch • SSTR • RET • Her-2 • Hormone receptors (E/P)
Targeting the NET cell surface: new targets to explore
X Symposium GETNE Madrid, Oct 2014
The Christie NHS Foundation Trust
Notch
X Symposium GETNE Madrid, Oct 2014 Ranganathan 2011
The Christie NHS Foundation Trust
• Selected population vs Unselected population
• Biomarkers interpretation across diferent malignancies
• Translational research
• Trials end-points: adjusted to the scenario
• “New” techniques • Epigenetics and sequencing
How can we do it “right”?
X Symposium GETNE Madrid, Oct 2014
The Christie NHS Foundation Trust
NET sequencing
X Symposium GETNE Madrid, Oct 2014
• Sequencing of small bowel NETs • Banck et al, Journal of Clinical Investigation 2013 (n=48) • Francis et al, Nature Genetics 2013 (n=55)
• Sequencing of pNETS • Jiao et al, Science 2011 (n=68) • Cao et al, Nature communications 2013 (39 insulinomas)
• Sequencing of lung NETs • Swarts et al, Carcinogenesis 2013 (n=65)
The Christie NHS Foundation Trust
Epigenetics
X Symposium GETNE Madrid, Oct 2014 Leotlela et al. Endocrine-Related Cancer 2003
The Christie NHS Foundation Trust
Molecular profiling of small intestinal neuroendocrine tumours
X Symposium GETNE Madrid, Oct 2014
• Small bowel NET (n = 49) and normal small intestine (n = 21)
• 130,083 significant methylation variable positions • including 1841 sites hypermethylated by >30% in tumour
compared to normal tissue • 626 genes were found to have significant >3 fold differential
expression between NET and normal tissue
• 11 candidate genes where altered methylation and expression was significant and concordant
Karpathakis et al, ESMO 2014
The Christie NHS Foundation Trust
GIPR: gastic inhibitory polypeptide receptor
X Symposium GETNE Madrid, Oct 2014 Karpathakis et al, ESMO 2014
The Christie NHS Foundation Trust
GIPR: gastic inhibitory polypeptide receptor
X Symposium GETNE Madrid, Oct 2014 Karpathakis et al, ESMO 2014
The Christie NHS Foundation Trust
GIPR, new biomarker?
X Symposium GETNE Madrid, Oct 2014 Karpathakis et al, ESMO 2014
• Aberrant methylation of GIPR correlated with higher expression
• Expression in small bowel NET was higher than in normal intestinal tissue
• Further validation is needed, but may be a new biomarker for small bowel NET
• Therapeutic or clinical impact: unknown
The Christie NHS Foundation Trust
Take home messages
X Symposium GETNE Madrid, Oct 2014 Leotlela et al. Endocrine-Related Cancer 2003
• How can we improve our results?
• Multiple targets • Need for involvement of basic research and
translational research • “New” techniques
• Trial design • End points • Patient selection
• Never give up!
The Christie NHS Foundation Trust
• ESMO Translational Program
• Pancreatic Cancer Research Fund
Aknowledgement
X Symposium GETNE Madrid, Oct 2014
The Christie NHS Foundation Trust
Any questions?
X Symposium GETNE Madrid, Oct 2014