Table 1 Summary of the agents targeting for CSCs in clinical and preclinical

Surface Marker Inhibitors

 Bivatuzumab mertansine

CD44v6

Breast Cancer

I

24 participants

NCT02254005

Completed

Head and Neck Cancer

I

31 participants

NCT02254018

Completed

 Catumaxomab

EpCAM/CD3

Bladder Cancer

I

30 participants

NCT04819399

Recruiting

Ovarian Cancer

II

47 participants

NCT00377429

Completed

Colon Cancer, Breast Cancer

II

258 participants

NCT00836654

Completed

Gastric Cancer

II

70 participants

NCT00464893

Completed

Stomach Cancer

III

282 participants

NCT04222114

Recruiting

 CC-90002

CD47

Hematologic Cancer

I

60 participants

NCT02367196

Completed

 CSL362

CD123

AML

I

30 participants

NCT01632852

Completed

 Talacotuzumab (formerly CSL362)

CD123

AML

III

326 participants

NCT02472145

Completed

 Magrolimab (Hu5F9-G4)

CD47

Solid Tumors

I

88 participants

NCT02216409

Completed

Ovarian Cancer

I

34 participants

NCT03558139

Completed

AML

I

20 participants

NCT02678338

Completed

Large B Cell Lymphoma

I

30 participants

NCT03527147

Completed

Bladder Cancer

II

645 participants

NCT03869190

Recruiting

 IBI188

CD47

Advanced Malignancies

I

20 participants

NCT03763149

Completed

Solid Tumors

I

120 participants

NCT04861948

Recruiting

Acute Myeloid Leukemia

I

126 participants

NCT04485052

Recruiting

 IMGN632

CD123

Blastic Plasmacytoid DC Neoplasm

I

252 participants

NCT03386513

Recruiting

AML

II

274 participants

NCT04086264

Recruiting

 IMGN779

CD33

AML

I

62 participants

NCT02674763

Completed

 JNJ-63709178

CD123/CD3

AML

I

62 participants

NCT02715011

Completed

 Flotetuzumab(MGD006)

CD123

Myeloid Leukemia

II

25 participants

NCT04582864

Recruiting

Hematologic Cancer

I

40 participants

NCT04681105

Recruiting

 Gemtuzumab Ozogamicin

CD33

AML

I

24 participants

NCT04070768

Recruiting

Blood Cancers

II

100 participants

NCT03589729

Recruiting

AML

III

168 participants

NCT00962767

Completed

 RO5429083

CD44

Solid Tumors

I

65 participants

NCT01358903

Completed

AML

I

44 participants

NCT01641250

Completed

 SGN-CD123A

CD123

AML

I

17 participants

NCT02848248

Terminated

 SRF231

CD47

Solid Tumors

Hematologic Neoplasmas

I

148 participants

NCT03512340

Completed

 Tagraxofusp (SL-401)

IL3R-targeting Fusion Protein

Dendritic Cell Neoplasm

II

40 participants

NCT04216524

Recruiting

CD123

Acute Myeloid Leukemia

II

50 participants

NCT04342962

Recruiting

CML

II

130 participants

NCT02268253

Recruiting

 Talacotuzumab

CD123

AML

III

326 participants

NCT02472145

Completed

 TTI-621

CD47

Hematologic Cancer

I

260 participants

NCT02663518

Recruiting

Multiple Myeloma

I

40 participants

NCT05139225

Recruiting

Leiomyosarcoma

I

80 participants

NCT04996004

Recruiting

 Vadastuximab Talirine (SGN-CD33A)

CD33

AML

I

116 participants

NCT02326584

Completed

 XmAb14045

CD123

Hematologic Cancer

I

120 participants

NCT02730312

Completed

 4SCAR-T

CD22/CD123/CD38/ CD10/CD20

CD19 Negative B-cell Malignancies

I II

100 participants

NCT04430530

Recruiting

 Anti-CD33 CAR NK cells

CD33

AML

I

27 participants

NCT05008575

Recruiting

 4SCAR T cells

CD44v6

Breast Cancer

I II

100 participants

NCT04430595

Recruiting

Transcriptional factor inhibitors

 Ivermectin

Oct4/Sox2/Nanog

Breast Cancer

[334]

Preclinical

Solid Tumors

[335]

Preclinical

 ZF-5985KD

Sox2

Breast Cancer

[336]

Preclinical

 Peptide aptamer P42

Sox2

Esophageal squamous cell Carcinoma

[337]

Preclinical

 Simvastatin

KLF4

Osteosarcoma

[338]

Preclinical

 D347-2761

c-Myc

Osteosarcoma

[339]

Preclinical

 T417

PBX1

Ovarian Cancer

[340]

Preclinical

Metabolism inhibitors

 2-deoxy-D-glucose

Glycolysis

Solid Tumors

I

50 participants

NCT00096707

Completed

Prostate Cancer

I II

12 participants

NCT00633087

Terminated

 CB-839

Glutaminolysis

Solid Tumors

I

210 participants

NCT02071862

Completed

Hematological Tumors

I

25 participants

NCT02071888

Completed

 TVB-2640

Lipogenesis

Breast Cancer

II

80 participants

NCT03179904

Recruiting

 Omeprazole

Lipogenesis

Breast Cancer

II

42 participants

NCT02595372

Completed

 PT2385

HIF

Renal cell Carcinoma

I

80 participants

NCT04989959

Recruiting

Glioblastoma

II

24 participants

NCT03216499

Completed

 Metformin

Glycolysis

Hepatocellular Carcinoma

[341]

Preclinical

Prostate Cancer

[342]

Preclinical

 Epigallocathechine gallate

Glycolysis

Pancreatic Cancer

[343]

Preclinical

 R-HepG2

Glutaminolysis

Hepatocellular Carcinoma

[234]

Preclinical

 alpha-ketoglutarate

Glutaminolysis

Colorectal Carcinoma

[235]

Preclinical

 GSK864

Glutaminolysis

Glioblastoma

[344]

Preclinical

 PT2399

HIF

Renal cell Carcinoma

[345]

Preclinical

 32-134D

HIF

Hepatocellular Carcinoma

[346]

Preclinical

Shh inhibitor

 BMS-833923 (XL139)

SMO

Solid Tumor

I

12 participants

NCT01413906

Completed

Basal Cell Carcinoma

I

53 participants

NCT00670189

Completed

Stomach/Esophageal Cancer

I

39 participants

NCT00909402

Completed

Small Cell Lung Carcinoma

I

5 participants

NCT00927875

Completed

Leukemia

I II

33 participants

NCT01218477

Completed

 Glasdegib

SMO

AML

III

730 participants

NCT03416179

Completed

Soft Tissue Sarcoma

III

960 participants

NCT03784014

Recruiting

 LDE225

SMO

Prostate Cancer

I

14 participants

NCT02111187

Completed

Ovarian Cancer

I

15 participants

NCT02195973

Completed

Solid Tumors

I

30 participants

NCT01954355

Completed

Pancreatic Cancer

I

18 participants

NCT01487785

Completed

Myeloid Malignancies

I

63 participants

NCT02129101

Completed

Medulloblastoma

II

22 participants

NCT01708174

Completed

 Vismodegib

Hedgehog

Solid Tumors

I

52 participants

NCT01209143

Completed

Colorectal Cancer

II

199 participants

NCT00636610

Completed

 Vismodegib

Hedgehog

Ovarian Cancer

II

104 participants

NCT00739661

Completed

Pancreatic Cancer

II

118 participants

NCT01064622

Completed

Gastric Cancer

II

124 participants

NCT00982592

Completed

Basal Cell Carcinoma

IV

30 participants

NCT03610022

Recruiting

Notch inhibitors

 AL101

γ secretase

Adenoid Cystic Carcinoma

I

12 participants

NCT04973683

Recruiting

Breast Cancer

II

67 participants

NCT04461600

Recruiting

 BMS-906024

NOTCH

Solid Tumors

I

94 participants

NCT01292655

Completed

Lymphoblastic Leukemia, Acute T-cell

I

31 participants

NCT01363817

Completed

 CB-103

NOTCH

Solid Tumours/Haematological Malignancies

I II

200 participants

NCT03422679

Recruiting

Breast Cancer

II

80 participants

NCT04714619

Active, not recruiting

 LY3039478

γ secretase

Solid Tumor

I

94 participants

NCT02784795

Completed

Plasma Cell Myeloma

I

18 participants

NCT03502577

Suspended

T-cell Lymphoblastic Lymphoma

I

36 participants

NCT02518113

Completed

 MK-0752

γ secretase

Pancreatic Cancer

I

44 participants

NCT01098344

Completed

Breast Cancer

IV

22 participants

NCT00756717

Completed

 RO4929097

γ secretase

Sarcoma

I II

78 participants

NCT01154452

Completed

 RO4929097

γ secretase

Colorectal cancer

II

37 participants

NCT01116687

Completed

Pancreatic Cancer

II

18 participants

NCT01232829

Completed

NSCL

II

7 participants

NCT01070927

Completed

 Brontictuzumab(OMP-52M51)

NOTCH

Colorectal Cancer

I

7 participants

NCT03031691

Completed

Lymphoid Malignancies

I

24 participants

NCT01703572

Completed

Solid Tumors

I

48 participants

NCT01778439

Completed

 Demcizumab (OMP-21M18)

NOTCH 1

Solid Tumors

I

29 participants

NCT02722954

Completed

NSCL

I

50 participants

NCT01189968

Completed

Pancreatic Cancer

II

207 participants

NCT02289898

Completed

 ABL001

DLL4

Solid Tumors

I

45 participants

NCT03292783

Completed

WNT signaling

 CWP232291

β-catenin

Multiple Myeloma

I

25 participants

NCT02426723

Completed

 CWP232291

β-catenin

AML

I

69 participants

NCT01398462

Completed

 PRI-724

CBP/β-catenin

Pancreatic Cancer

I

20 participants

NCT01764477

Completed

Myeloid Malignancies

I II

49 participants

NCT01606579

Completed

 OMP-54F28

Frizzled8

Liver Cancer

I

10 participants

NCT02069145

Completed

Pancreatic Cancer

I

26 participants

NCT02050178

Completed

Ovarian Cancer

I

37 participants

NCT02092363

Completed

 OMP-54F28

Frizzled8

Solid Tumors

I

26 participants

NCT01608867

Completed

 Vantictumab (OMP-18R5)

Frizzled7

Pancreatic Cancer

I

30 participants

NCT02005315

Completed

Breast Cancer

I

37 participants

NCT01973309

Completed

Solid Tumors

I

35 participants

NCT01345201

Completed

 ETC-1922159

Porcupine

Solid Tumors

I

89 participants

NCT02521844

Recruiting

 LGK974

Porcupine

Solid Tumors

I

185 participants

NCT01351103

Recruiting

Colorectal Cancer

I II

20 participants

NCT02278133

Completed

TGF-β inhibitors

 AVID200

TGFβ

Solid Tumor

I

19 participants

NCT03834662

Active, not recruiting

 LY3200882

TGFβRI

Solid Tumor

I

223 participants

NCT02937272

Active, not recruiting

 Fresolimumab (GC1008)

TGF-β

Renal Cell Carcinoma/Melanoma

I

29 participants

NCT00356460

Completed

NSCL

I II

24 participants

NCT02581787

Completed

Breast Cancer

II

23 participants

NCT01401062

Completed

Brain Tumors

II

12 participants

NCT01472731

Completed

Mesothelioma

II

14 participants

NCT01112293

Completed

 Galunisertib

Growth Factor-β Receptor I Kinase

Pancreatic Cancer

I

37 participants

NCT02734160

Completed

Solid Tumor

I II

41 participants

NCT02423343

Completed

Glioma

I II

75 participants

NCT01220271

Completed

Hepatocellular Carcinoma

II

204 participants

NCT01246986

Completed

 NIS793

TGF-β

Solid Tumor

I

120 participants

NCT02947165

Completed

Colorectal Cancer

II

266 participants

NCT04952753

Recruiting

Pancreatic Ductal Adenocarcinoma

III

490 participants

NCT04935359

Recruiting

 Vactosertib (TEW-7197)

TGF-β

Solid Tumor

I

35 participants

NCT02160106

Completed

Multiple Myeloma

I

18 participants

NCT03143985

Recruiting

Desmoid Tumor

I II

24 participants

NCT03802084

Recruiting

NSCL

II

55 participants

NCT04515979

Completed

JAK inhibitors

 AZD4205

Janus Kinase

NSCL

I II

10 participants

NCT03450330

Completed

T Cell Lymphoma

II

160 participants

NCT04105010

Recruiting

 SAR302503

JAK2 V617F

Solid Tumor

I

60 participants

NCT01836705

Completed

Hematopoietic Neoplasm

II

97 participants

NCT01523171

Completed

 Ruxolitinib

JAK

Breast Cancer

II

29 participants

NCT01594216

Completed

AML

III

1000 participants

NCT03117751

Recruiting

 SB1518

FLT3

Lymphoma

I

35 participants

NCT00741871

Completed

AML

I

13 participants

NCT02323607

Completed

DNMT inhibitors

 Azacitidine

DNMT

AML

III

488 participants

NCT01074047

Completed

 Decitabine

DNMT

Thyroid Cancer

II

12 participants

NCT00085293

Completed

Solid Tumor

III

200 participants

NCT04292769

Recruiting

 Decitabine

DNMT

Ovarian cancer

II III

500 participants

NCT02159820

Recruiting

Hodgkin Lymphoma

II III

100 participants

NCT04510610

Recruiting

 Guadecitabine (SGI-110)

DNMT

Colorectal Cancer

I

18 participants

NCT01966289

Completed

MDS

I II

401 participants

NCT01261312

Completed

Ovarian Cancer

II

120 participants

NCT01696032

Completed

Hepatocellular Carcinoma

II

52 participants

NCT01752933

Completed

AML

III

302 participants

NCT02920008

Completed

 Disulfiram

DNMT1

Prostate Cancer

N/A

19 participants

NCT01118741

Completed

 Aza-TdC

DNMT1

Solid Tumor

I

50 participants

NCT03366116

Recruiting

 NTX-301

DNMT

Myeloid Malignancies

I

20 participants

NCT04167917

Recruiting

HDAC inhibitors

 Belinostat

Class I/II HDACs

Solid Tumors/Hematological Malignancies

I

27 participants

NCT01317927

Completed

Breast Cancer/Prostate Cancer/Ovarian Cancer

I

25 participants

NCT04703920

Recruiting

NSCL

I

28 participants

NCT00926640

Completed

Multiple Myeloma

II

25 participants

NCT00131261

Completed

Melanoma

II

32 participants

NCT05170334

Recruiting

 Entinostat

Class I HDACs

Breast Cancer

I

61 participants

NCT02820961

Completed

CNS Tumor/Solid Tumor

I II

128 participants

NCT03838042

Recruiting

Bladder Cancer

II

20 participants

NCT03978624

Recruiting

acute myeloid leukemia

II

24 participants

NCT00462605

Completed

Melanoma

II

14 participants

NCT03765229

Recruiting

 Givinostat (ITF2357)

Class I/II HDACs

Hodgkin’s Lymphoma

I II

24 participants

NCT00792467

Completed

 Panobinostat (LBH589)

pan-DACi

Solid Tumor

I

25 participants

NCT01007968

Completed

Lung Cancer/Head and Neck Cancer

I

44 participants

NCT00738751

Completed

 Panobinostat (LBH589)

pan-DACi

Multiple Myeloma

III

767 participants

NCT01023308

Completed

Hodgkin’s Lymphoma

III

41 participants

NCT01034163

Completed

 Pracinostat (SB939)

Class I/II HDACs

Solid Tumor

I

39 participants

NCT00504296

Completed

 Pracinostat (SB939)

Class I/II HDACs

Prostate Cancer

II

32 participants

NCT01075308

Completed

AML

II

50 participants

NCT01912274

Completed

Sarcoma

II

24 participants

NCT01112384

Completed

 Romidepsin

Class I HDACs

Solid Tumors

I

18 participants

NCT01537744

Completed

Lung Cancer

I

34 participants

NCT00037817

Completed

 Romidepsin

Class I HDACs

Pancreas Cancer

I II

75 participants

NCT04257448

Recruiting

T-Cell Lymphoma

III

271 participants

NCT01482962

Completed

 Valproic Acid

Class I/II HDACs

Solid Tumors

I

36 participants

NCT00529022

Completed

NSCL

I

25 participants

NCT00084981

Completed

AML

I II

36 participants

NCT00995332

Completed

Cervical Cancer

II

18 participants

NCT00404326

Completed

 Valproic Acid

Class I/II HDACs

Glioma

III

167 participants

NCT03243461

Recruiting

Childhood Ependymoma

III

480 participants

NCT02265770

Recruiting

 Vorinostat

Class I/II HDACs

Solid Tumors

I

28 participants

NCT00121277

Completed

Gastric Cancer

I II

45 participants

NCT01045538

Completed

Mesothelioma

III

661 participants

NCT00128102

Completed

Multiple Myeloma

III

637 participants

NCT00773747

Completed

AML

III

754 participants

NCT01802333

Completed

 CHR-3996

HDAC

Solid Tumors

I

40 participants

NCT00697879

Completed

 Chidamide

Class I HDACs

Cervical Cancer

I

40 participants

NCT04651127

Recruiting

AML

I II

250 participants

NCT03031262

Recruiting

 Chidamide

Class I HDACs

Sarcoma

II

53 participants

NCT04025931

Recruiting

Neuroendocrine Tumors

II

23 participants

NCT05113355

Recruiting

 Quisinostat

HDACs

NSCL

I

51 participants

NCT02728492

Completed

Lymphoma

I

92 participants

NCT00677105

Completed

Multiple Myeloma

I

18 participants

NCT01464112

Completed

 AR-42

Pan-DAC Inhibitor

Plasma Cell Myeloma

I

9 participants

NCT02569320

Completed

AML

I

13 participants

NCT01798901

Completed