Table 2 CSC-targeting agents

TGF-β signaling

 Antisense oligonucleotides

Pancreatic neoplasms, Colorectal Neoplasms

AP 12009 (Trabedersen)

TGF-β2

Phase 1

NCT00844064

 TβR kinase inhibitors/small-molecule inhibitors

(1) Hepatocellular carcinoma

(2) Advanced or metastatic unresectable pancreatic cancer

(3) Rectal adenocarcinoma

(4) Advanced hepatocellular carcinoma

(5) Advanced hepatocellular carcinoma

(6) Metastatic cancer and advanced or metastatic unresectable pancreatic cancer

(7) Metastatic pancreatic cancer

(8) Advanced refractory solid tumors; Hepatocellular carcinoma

(9) Metastatic pancreatic cancer

LY2157299

(Galunisertib)

TβRI

(1) Phase 1

(2) Phase 1

(3) Phase 2

(4) Phase 2

(5) Phase 2

(6) Phase 1b/2

(7) Phase 1

(8) Phase 1b/2

(9) Phase 1

(1) Sorafenib

(2) Galunisertib

(3) Capecitabine, Fluorouracil

(4) Sorafenib

(5) Sorafenib, Ramucirumab

(6) Gemcitabine

(7) Durvalumab

(8) Nivolumab

(9) Durvalumab

(1) NCT02240433

(2) NCT02154646

(3) NCT02688712

(4) NCT02178358

(5) NCT01246986

(6) NCT01373164

(7) NCT02734160

(8) NCT02423343

(9) NCT02734160

Wnt signaling

 β-catenin inhibitors

(1) Advanced pancreatic cancer; Metastatic pancreatic cancer; Pancreatic adenocarcinoma

(2) Hepatitis C virus-infected cirrhosis

(3) Colorectal adenocarcinoma; Stage IVA colorectal cancer; Stage IVB colorectal cancer

ICG-001(PRI-724)

CBP/β-Catenin

(1) Phase 1

(2) Phase 1

(3) Phase 2

(1) Gemcitabine

(3) Bevacizumab,

Leucovorin,

Oxaliplatin,

Fluorouracil

(1) NCT01764477

(2) NCT02195440

(3) NCT02413853

 Wnt antibodies

(1) Hepatocellular carcinoma

(2) Pancreatic cancer; Stage IV pancreatic cancer

Ipafricept (OMP-54F28)

Fzd8-Fc fusion protein

(1) Phase 1

(2) Phase 1

(1) Sorafenib

(2) Nab-Paclitaxel

Gemcitabine

(1) NCT02069145

(2) NCT02050178

(1) Colorectal cancer

(2) Metastatic colon cancer

Foxy-5

WNT5a receptor

(1) Phase 1

(2) Phase 1

(1) NCT02020291

(2) NCT02655952

 Wnt antibodies

Pancreatic cancer

Vantictumab (OMP-18R5)

Frizzled receptor

Phase 1

Nab-Paclitaxel and Gemcitabine

NCT02005315

 DKK1 antibodies

(1) Hepatocellular carcinoma

(2) Esophageal neoplasms; Adenocarcinoma of the gastroesophageal junction; gastroesophageal cancer; Gastric adenocarcinoma

(3) Carcinoma of intrahepatic and extra-hepatic biliary system;

Bile duct cancer;

Cholangiocarcinoma

DKN-01

DKK1

(1) Phase 1/2

(2) Phase 1

(3) Phase 1

(1) Sorafenib

(2) Paclitaxel or pembrolizumab

(3) Gemcitabine and cisplatin

(1) NCT03645980

(2) NCT02013154

(3) NCT02375880

 Porcupine inhibitors

(1) Metastatic colorectal cancer

(2) Pancreatic cancer; Esophageal squamous cell cancer

LGK974 (WNT974)

Porcupine

(1) Phase 1

(2) Phase 1

(1) LGX818, Cetuximab

(2) PDR001

(1) NCT02278133

(2) NCT01351103

Colorectal adenocarcinoma;

Gastric adenocarcinoma; Pancreatic adenocarcinoma; Bile duct carcinoma; Hepatocellular carcinoma; Esophageal carcinoma;

Gastrointestinal cancer

CGX1321

Porcupine

Phase 1

Pembrolizumab

NCT03507998

Notch signaling

 DLL-4 antibody

(1) Metastatic pancreatic ductal adenocarcinoma

(2) Locally advanced or metastatic pancreatic cancer

(3) Colorectal cancer

Demcizumab (OMP-21M18)

DLL4

(1) Phase 2

(2) Phase 1

(3) Phase 1

(1) Gemcitabine, Abraxane®

(2) Gemcitabine, Abraxane®

(1) NCT02289898

(2) NCT01189929

(3) NCT01189942

 Notch receptor antibody

Untreated stage IV pancreatic cancer

Tarextumab

(OMP-59R5)

Notch2,

Notch3

Phase 1/2

Nab-Paclitaxel, Gemcitabine

NCT01647828

Metastatic colorectal cancer

Brontictuzumab

(OMP-52M51)

Notch1

Phase 1

Trifluridine or tipiracil

NCT03031691

 γ-secretase inhibitor

Pancreatic cancer

MK-0752

γ-secretase

Phase 1

Gemcitabine hydrochloride

NCT01098344

 γ-secretase inhibitor

(1) Metastatic pancreas cancer

(2) Metastatic colorectal cancer

(3) Metastatic colorectal cancer

(4) Metastatic colorectal cancer

RO4929097

(R4733)

γ-secretase

(1) Phase 2

(2) Phase 2

(3) Phase 1

(4) Phase 2

(2) FOLFOX regimen,

Bevacizumab,

Oxaliplatin,

leucovorin calcium,

fluorouracil

(3) Cetuximab

(1) NCT01232829

(2) NCT01270438

(3) NCT01198535

(4) NCT01116687

Hedgehog signaling

 SMO inhibitor

(1) Metastatic pancreatic adenocarcinoma

(2) Metastatic colorectal cancer

(3) Pancreatic adenocarcinoma

(4) Metastatic pancreatic cancer or solid tumors

(5) Pancreatic ductal adenocarcinoma

(6) Metastatic colorectal cancer

(7) Recurrent or metastatic pancreatic cancer

Vismodegib (GDC-0449)

SMO

(1) Phase 2

(2) Phase 2

(3) Phase 1

(4) Phase 1

(5) Phase II

(6) Phase II

(7) Phase II

(1) Gemcitabine, nab-paclitaxel

(2) Bevacizumab,

Modified FOLFOX,

FOLFIRI

(3) Gemcitabine

(4) Erlotinib, gemcitabine

(6) Vismodegib, FOLFOX, FOLFIRI, Bevacizumab

(7) Gemcitabine hydrochloride

(1) NCT01088815

(2) NCT00636610

(3) NCT01713218

(4) NCT00878163

(5) NCT01096732

(6) NCT00959647

(7) NCT01064622

Metastatic gastric, gastroesophageal, esophageal

adenocarcinomas

BMS-833923 (XL139)

Phase 1

Cisplatin,

capecitabine

NCT00909402

Esophageal cancer

Taladegib (LY2940680)

Phase 1/2

Paclitaxel, carboplatin, radiation

NCT02530437

(1) Metastatic pancreatic cancer

(2) Advanced pancreatic adenocarcinoma

Patidegib (IPI-926)

(1) Phase 1

(2) Phase 1

(1) Gemcitabine

(2) FOLFIRINOX

(1) NCT01130142

(2) NCT01383538

 SMO inhibitor

(1) Esophageal cancer

(2) Esophageal Cancer

(3) Locally Advanced Squamous Esophageal Cancer

Itraconazole

SMO

(1) Phase 1

(2) Phase 2

(3) Phase 2

(1) NCT02749513

(2) NCT04018872

(3) NCT04481100

(1) Pancreatic cancer

(2) Pancreatic cancer

Saridegib (IPI-926)

(1) Phase 1

(2) Phase 1/2

(1) 5-fluorouracil,

Leucovorin,

Irinotecan, Oxaliplatin

(2) Gemcitabine

(1) NCT01383538

(2) NCT01130142

(1) Resectable pancreatic adenocarcinoma

(2) Advanced or metastatic HCC

(3) Esophageal cancer

(4) Advanced pancreatic cancer

(5) Pancreatic cancer

(6) Pancreatic cancer

(7) Pancreatic cancer

(8) Resectable pancreatic cancer

Sonidegib (LDE225)

(1) Phase 1/2

(2) Phase 1

(3) Phase 1

(4) Phase 1

(5) Phase 1/2

(6) Phase 1

(7) Phase 1

(8) Phase 1

(1) Gemcitabine,

nab-paclitaxel

(3) Everolimus

(4) Fluorouracil, leucovorin, oxaliplatin, irinotecan

(5) Gemcitabine,

nab-paclitaxel

(6) Gemcitabine

(7) Fluorouracil; Leucovorin; Oxaliplatin;

Irinotecan

(1) NCT01431794

(2) NCT02151864

(3) NCT02138929

(4) NCT01485744

(5) NCT02358161

(6) NCT01487785

(7) NCT01485744

(8) NCT01694589

Hippo signaling

 YAP inhibitor

Pancreatic cancer non-resectable

Verteporfin

YAP

Phase 2

Photodynamic therapy

NCT03033225

CSC surface markers

 Anti-CD44 antibody

Malignant solid tumor

RO5429083

CD44

Phase 1

NCT01358903

 CD44v6 inhibitor

Malignant solid tumor

AMC303

CD44v6

Phase 1

NCT03009214

 Anti-CD47 antibody

(1) Colorectal neoplasms/Solid tumors

(2) Advanced malignancies

(3) Advanced solid cancers

(4) Solid tumor

(1) Hu5F9-G4

(2) IBI188

(3) SRF231

(4) AO-176

CD47

(1) Phase 1

(2) Phase 1

(3) Phase 1

(4) Phase 1/2

(1) Cetuximab

(1) NCT02953782

(2) NCT03763149

(3) NCT03512340

(4) NCT03834948

 Recombinant fusion protein binding CD47

Solid tumor

TTI-621

CD47

Phase 1

Rituximab or Nivolumab

NCT02663518

 Anti-EpCAM antibody

(1) Gastric cancer, Gastric adenocarcinoma

(2) Gastric Adenocarcinoma With Peritoneal Carcinomatosis,

Siewert Type II/III Adenocarcinoma of Esophagogastric Junction With Peritoneal Carcinomatosis

Catumaxomab

EpCAM

(1) Phase 2

(2) Phase 2

(1) NCT00464893

(2) NCT01504256