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
Survival probability (%)
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?)
T UMOURS 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