Adenocarcinoma pancreatico:

Prospettive degli studi di fase I

Stefano Cascinu

Modena Cancer Center Modena, Italy

Fasi I e adenocarcinoma pancreatico:

• Necessità di una terapia sistemica efficace

• La chemioterapia è la base della attuale terapia standard:

– Gem/abraxane

– FOLFIRINOX

Quale bersaglio?

• Cellule tumorali con relative mutazioni

• Stroma

• immunità

Fasi I e adenocarcinoma pancreatico:

Come disegnare uno studio di fase I nell’adenocarcinoma pancreatico?

Fasi I in corso

• BK-8040 (CXCR4 antagonist)

• Afatinib (irreversible EGFR Family Inhibitor)

• Gedatosilisib (Dual Inhibitor of PI3K and mTOR inhibitor)

• Defactinib (FAK focal adhesion kinase) inhibitor)

• Veliparib (PARP inhibitor)

High prevalence: KRAS, TP53, CDKN2A, & SMAD4

Other mutations: High variability and low prevalence

Pancreatic Cancer Is Genetically Diverse

Ras Mutations and Tumor Type

K ≈ 30-50 Lung (NSC) H, K <5 Breast N >50 Bile Duct H, N, K ≈ 25 Head & Neck H, N, K ≈ 50-80 Thyroid

≈ 20-86 Cervix K ≈ 40-50 Colon K ≈ 80 Pancreas

Predominant Ras Mutation % Ras Mutation Cancer

Phase II study of refametinib (BAY 86-9766), an allosteric dual MEK 1/2 inhibitor, and gemcitabine in patients with unresectable, locally advanced or metastatic pancreatic cancer Jean-Luc Van Laethem1, Jacek Jassem2, Volker Heinemann3, Collin Weekes4, John Bridgewater5, Stefano Cascinu6, Bohuslav Melichar7, Marc Peeters8, Paul Ross9, Piotr Saramak10, Marius Giurescu11, Vittorio L Garosi12, Katrin Roth11, Anke Schulz11, Michael Teufel11, Barrett H Childs13 Hanno Riess14

Ras Mutations as a therapeutic target

PDAC carcinogenesis

Evidence that oncogenic K-RAS is not constitutively activated

PDAC, pancreatic ductal adenocarcinoma

Cancer Genome Atlas Research Network. Cancer Cell. 2017;32(2):185-203.

Recurrent Mutations in Pancreatic Cancer

• PDAC results from a large number of genetic mutations

• Gene mutations converge on limited number of pathways and processes

• Pathway components that are altered in any individual tumor vary widely

Discovery of agents that target altered pathways and processes may offer key nodals for therapy

Integrated Genomic Analysis Revealed Potential Novel Vulnerabilities

N = 456 PDAC tissues 32 recurrently mutated genes 10 pathways & processes

Bailey P, et al. Nature. 2016;531(7592):47-52.

P. Bailey

Genomic analyses identify 4 molecular subtypes of pancreatic cancer Nature 2016

protean, from Proteus with the meaning of "mutable", "capable of assuming many forms".

Pancreatic cancer: a “protean” disease

Proteus can foretell the future

but he will change his shape to

avoid having to. He answers only

to someone who is capable of

capturing him.

PDAC is characterized by low tumor

cellularity and a dense microenvironment

Neesse A, Ellenrieder V. Z Gastroenterol. 2015;53(4):337-338.

Rhim AD et al. Cell 2012

“HH and CXCL12 and the others”:

the bad company

Mesenchymal cancer cells

CD24+ cells

CD44+ cells

CD133+ cells

SHH

VEGF

IL-6

IGFB

SHH, PDGF, TGF-B, CXCL12

Epithelial cancer cells

Stellate

Cells

CAFs TGF-b CXCL12

CXCL12

IL-1β

IL-6 COX-2

K-Ras Mutation

Cellular necrosis, DAMPs

Andrikou, Cascinu, 2017

Targeting key signaling and transcription hubs: EMT

Napabucasin

Baumgart S, et al. Cancer Discov. 2014;4(6):688-701.

NFAT/STAT3 target genes: • PDL-1

• GM-CSF

• CXCL12

• CXCL5

• MMP11

• MMP1

• WNT1

• WNT10

• EGFR

• ...and stemness inhibition !

BBI608 (Napabucasin) = STAT3 Inhibitor

Phase Ib trial with napabucasin in combination with gemcitabine and nab-paclitaxel in patients with

metastatic pancreatic adenocarcinoma

N=41

Bekaii-Saab TS, et al. J Clin Oncol. 2017;35(suppl 4): Abstract 4106.

Promising activity in patients with refractory, heavily pretreated metastatic pancreatic cancer (N = 71); particularly, in patients who are taxane naïve. DCR was observed in 55 (77%), with 1 CR (1.4%) and 26 PR (37%) Treatment-related grade 3 adverse effects included diarrhea (4.9%), abdominal pain (4.9%), and nausea (2.4%), and were rapidly reversible

NCT02231723

NCT02993731

Phase III Study of BBI-608 Plus Nab-Paclitaxel With Gemcitabine in Adult Patients With Metastatic Pancreatic Adenocarcinoma

Open-label, multicenter, phase III study

- Recruiting

NCT02231723

Phase Ib Clinical Study of BBI-608 in Combination With Standard Chemotherapies in Adult Patients With Metastatic Pancreatic Adenocarcinoma

- Recruiting

Ongoing Clinical Trials With Napabucasin

Cancer Stem Cells markers expression and survival in resected pancreatic cancer patients

124 pts n. Pts

(%)

Median

OS

Group A

(score 0)

16

(12.9)

30.8

months

Group B

(score 1-2)

86

(69.4)

16.2

months

Group C

(score 3-4)

22

(17.7)

8.3

months

stam4 0 1 2

Overall Survival

0 20 40 60 80 100 120

100

80

60

40

20

0

Time

Surv

ival

pro

bab

ility

(%

)

Overall Survival (OS) of 124 resected pancreatic cancer patients according to expression of CSCs markers (CD133, CD24, CD44, OCT3/4)

Targeting the Tumor Microenvironment

Stroma cells CAF Stellate cells

ECM Hyaluronic acid collagen I-IV laminin, fibronectin

Stromal Signaling Hedgehog TGFβ

CTGF

Immune regulation PD-1/PD-L1 CTLA4 Treg, MDSC

Tumor stroma

Multifaceted Biology of PDA

Hidalgo M, et al. Clin Cancer Res. 2012;18(16):4249-4256. PDA, pancreatic ductal adenocarcinoma

Multifaceted Biology of PDA

Hidalgo M, et al. Clin Cancer Res. 2012;18(16):4249-4256. PDA, pancreatic ductal adenocarcinoma

La somministrazione cronica di inibitori di HH riduce lo stroma ma

non determina alcun vantaggio terapeutico. Vi è anzi un aumento di

aggressività del tumore (attività proliferativa; angiogenesi).

Alcuni problemi in più: l’immunoterapia

Impatto significativo: Melanoma, Rene, Polmone, Vescica, LH, tumori con MSI

• Marked immune dysfunction driven by

immunosuppressive cell types, tumor

promoting immune cells and

inflammatory cells.

• A subset of immune cells has been

shown to support the growth of

pancreatic cancer cells.

• The ligand PD-L1 is upregulated

in pancreatic cancer and it may

explain the immunosuppression

present in this neoplasia.

• Tumors evade the immune

system by preventing the

presence of T cells and NK

cells (stroma, inflammatory

cytokines?)

TUMOURS CAN BE CATEGORISED INTO THREE TYPES ACCORDING

TO THE T CELL PATTERN ASSOCIATED WITH THE TUMOUR

IMMUNE DESERT CD8+ T cells absent from tumour and periphery Increase number of antigen-specific T cells or increase antigen presentation

IMMUNE EXCLUDED CD8+ T cells accumulated but not efficiently infiltrated Bring T cells in contact with cancer cells

INFLAMED CD8+ T cells infiltrated, but non-functional Accelerate or remove brakes on T cell response

MSS Majority of tumours don’t have T cells ► fail to respond to monotherapy with PD-L1/PD-1 inhibitors Kim and Chen. Ann Oncol 2016 Hegde et al. Clin Cancer Res 2016

MSI-high (5%) More likely to respond to monotherapy PD-L1/PD-1 pathway inhibitors

fibroblast activation protein

stromal cell (mesenchymal origin) carcinoma-associated

fibroblasts

cancer cell

T cell

CXCL12 (SDF-1α)

CXCR4

high mobility group box 1

Exclusion of T cells in PDAC: the startrek effect

T cell exclusion

CXCR4 low

expression

Patients with pancreatic ductal adenocarcinoma (PDA) had no objective responses to anti CTLA-4 or PD-L1 monoclonal antibodies. Inhibition of CXCR4 restores the response to CTLA-4 or PD-L1.

CXCL12 (SDF-1α)

CXCR4

Aspetti etici

Lo sviluppo delle tecnologie

Cancer cell

CXCL12

CXCR4

Cancer cell

CXCR7

Esosomi come target terapeutico?

Activated Non activated