Targeting other receptors in NET´s cells...

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


We are living a transition era in NETs


“Classic” chemotherapy Targeted therapies

Hanahan et al, Cell, Vol. 100, 57–70, 2000


What do the targeted therapies target?


Joyce et al, Cancer Cell, 2005; DOI 10.1016/j.ccr.2005.05.024


• Tumoural cells • Membrane receptors • Intracellular pathways

• Peritumoural stroma

• Neoangiogenesis

• Inmune system

What do the targeted therapies target?


Hanahan et al, Cell, Vol. 100, 57–70, 2000


• Somatostatin analogues: SSTR analogues

Targeting the NET cell: current status


Octreotide (PROMID)

Lanreotide (Clarinet)

O Abdel-Rahman et al, in press


• Intracellular pathways

Targeting the NET cell: current status


Everolimus (mTOR)

Sunitinib (Angiogenesis)

A Lamarca et al, in press


Targeting the NET cell


• New targets in the NET cell surface


Potential new cell surface targets

X Symposium GETNE Madrid, Oct 2014 Rindi er al, Nature Reviews 2011.


• 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



• Trastuzumab (mAb)

• Lapatinib (TKI)

• HER2 overexpression

• Breast cancer • Gastric cancer


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


cKIT


Metastases and cell proliferation

Imatinib Oral TKI (cKIT,

PDGFR)

GIST

High mutation rate of cKIT or PDGFRA

Vidwans et al, http://therapy.collabrx.com/


• 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


• 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


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


EGFR


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)


EGFR: Gefitinib


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 pattern…


FAILURE


• Selected population vs Unselected population

• Biomarkers interpretation across different malignancies

• Trials end-points: adjusted to the scenario

What are we doing “wrong”?





Targeting the NET cell surface: new targets to explore



cMET


Journal of Clinical Oncology, Vol 29, No 36 (December 20), 2011: pp 4837-4838


• 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


Sennino et al, Cancer Res. 2013 June; doi:10.1158/0008-5472.CAN-12-2160.


cMET in lung NETs


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)


Wnt


• Activation • APC mut • βCatenin mut • Wnt inhibitors

methylation • Others

pathways components overespression

Nibaldo, DOI: 10.5772/54606


• 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


Notch

X Symposium GETNE Madrid, Oct 2014 Ranganathan 2011


• 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”?



NET sequencing


• 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)


Epigenetics

X Symposium GETNE Madrid, Oct 2014 Leotlela et al. Endocrine-Related Cancer 2003


Molecular profiling of small intestinal neuroendocrine tumours


• 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


GIPR: gastic inhibitory polypeptide receptor

X Symposium GETNE Madrid, Oct 2014 Karpathakis et al, ESMO 2014


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


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!


• ESMO Translational Program

• Pancreatic Cancer Research Fund

Aknowledgement



Any questions?


Targeting other receptors in NET´s cells...

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