Section 4.2: Agents targeting CSC-associated signaling pathways in clinical trials (from DOI: 10.1038/s41392-020-0110-5)
From publication: "Targeting cancer stem cell pathways for cancer therapy" published as Signal Transduct Target Ther; 2020 ; 5 8; DOI: https://doi.org/10.1038/s41392-020-0110-5
Section 4.2: Agents targeting CSC-associated signaling pathways in clinical trials
The signaling pathways that regulate the maintenance and survival of CSCs have become targets for cancer treatment. At present, the main signaling pathways are the Wnt, Notch, and Hh signaling pathways, as well as the TGF-beta, JAK-STAT, PI3K, and NF-kappaB signaling pathways. These pathways often interact with each other during tumor development and in CSCs. Considerable progress has been made in early clinical trials for Notch and Hh pathway inhibitors, while targeting the Wnt pathway has proven to be difficult.
The Notch signaling pathway plays an important role in the maintenance of CSCs and can induce CSC differentiation. Abnormal activity of the Notch signaling pathway has been observed in many cancers, such as leukemia, glioblastoma, breast cancer, lung cancer, ovarian cancer, pancreatic cancer, and colon cancer. At present, there are three major clinical methods used to inhibit Notch signaling, secretase inhibition (gamma-secretase inhibitor (GSI)), Notch receptor or ligand antibodies, and combination therapy with other pathways. For example, GSIs have been tested in clinical trials. Among them, MK-0752 (NCT00100152) was the first GSI used to treat T cell acute lymphoblastic leukemia in children in a phase I trial. However, the study was terminated because of poor results. MK-0752 also had no clinical activity in extracranial solid tumors in subsequent phase II trials. Only one complete response with interdegenerative astrocytoma and SD extension out of 10 patients with different types of glioma was observed. MK-0752 is well tolerated and shows targeted inhibition in recurrent pediatric central nervous system tumors. In addition, combining MK-0752 with cisplatin treatment for ovarian cancer, docetaxel treatment for locally advanced or metastatic breast cancer, and gemcitabine treatment for ductal adenocarcinoma of the pancreas has shown good efficacy. However, the clinical effect was minimal in patients with advanced solid tumors, including metastatic pancreatic cancer.
In addition, RO4929097, another selective GSI, showed good anti-tumor activity in preclinical and early trials, but was not good for metastatic colorectal cancer, metastatic pancreatic adenocarcinoma, or recurrent platinum-resistant ovarian cancer. Combinations of RO4929097 with gemcitabine, temsirolimus, cediranib, or capecitabine in advanced solid tumors, as well as with bevacizumab in recurrent high-grade glioma, are well tolerated and have modest clinical benefits. However, NCT01154452, the combination of RO4929097 with vismodegib and vismodegib alone for patients with advanced osteosarcoma, showed no significant difference in a phase Ib trial. The third oral GSI, PF-03084014, had good efficacy in desmoid tumors either in phase I or subsequent phase II studies. Preliminary evidence of its clinical efficacy was demonstrated in patients with solid tumors, as well as in patients with recurrent acute T cell lymphoblastic leukemia. Other selective GSIs, such as BMS-906024 (NCT01292655), BMS-986115 (NCT01986218), CB-103 (NCT03422679), LY3039478 (NCT02836600), and LY900009 (NCT01158404), have also entered the clinical trial stage, and the results still need to be verified.
DLL4 plays a vital role in regulating tumor angiogenesis. Therefore, targeting DLL4 is another strategy to block Notch signaling, and this is being tested in the clinic. Demcizumab (OMP-21M18), a humanized IgG2 mAb that targets DLL4 and blocks its interactions with Notch receptors, was tested in a phase I dose escalation study with 55 patients with previously treated solid tumors. The results have shown that demcizumab had good efficacy against solid tumors, but was not good for metastatic pancreatic cancer treatment when combined with gemcitabine and Abraxane (NCT02289898). NCT02259582, a combination of demcizumab with carboplatin and pemetrexed to treat lung cancers (DENALI study), is ongoing in another phase II study. Enoticumab, another fully human IgG1 antibody against DLL4, has promising activity in phase I clinical trials for advanced solid malignancies.
Activation of Hh signaling has been implicated in a variety of cancers. Activation of Hh signaling in CSCs contributes to CSC stemness, chemoresistance, and metastatic dissemination. The Hh signaling pathway mainly regulates target gene expression via smoothened (SMO)-mediated nuclear transfer of transcription factors. Three oral SMO antagonists, vismodegib (GDC-0449), sonidegib (LDE225), and glasdegib (PF-04449913), have been approved by the Food and Drug Administration (FDA) and show significant activity in locally advanced and metastatic basal cell carcinoma, as well as in AML. Vismodegib was the first proposed Hh pathway inhibitor in cancer research and is approved by the FDA for local or advanced metastatic basal cell carcinoma treatment. Subsequently, phase I and phase II trials targeting recurrent medulloblastoma have shown that the progression-free survival (PFS) of Shh-mb patients treated with vismodegib is longer and more effective than that of non-Shh-mb patients. Vismodegib even has better activity in patients with recurrent Shh-mb but not in patients with recurrent non-Shh-mb. Vismodegib has also been tested in metastatic colorectal cancer, pancreatic cancer, chondrosarcoma, relapsed/refractory NHL, CLL, and ovarian cancer. Disappointingly, these treatments with vismodegib have not resulted in better survival.
Sonidegib was the second SMO antagonist approved for the treatment of locally advanced basal cell carcinoma that recurred after surgery or radiotherapy and is not suitable for surgery or radiation therapy. In addition, the results of a multicenter, randomized, double-blind phase II trial have shown that 200 mg sonidegib for patients with advanced basal cell carcinoma is the most clinically appropriate dose.
In a phase I study of a 3 + 3 dose escalation to treat small-cell lung cancer patients, sonidegib combined with cisplatin and etoposide sustained PFS in patients with Sox2 amplification. These combinations in a phase II trial for patients with recurrent medulloblastoma resulted in a complete or partial response in 50% of patients and have been used for other cancer treatments in phase I/II clinical trials, such as NCT02111187 for prostate cancer, NCT02027376 for breast cancer, and NCT02195973 for recurrent ovarian cancer.
Glasdegib was the first Hh pathway inhibitor approved for the treatment of AML in patients older than 75 years or those unable to use intensive induction chemotherapy and showed good safety and tolerability in a phase I trial for patients with partial hematologic malignancies in Japan. In a phase II trial, glasdegib combined with cytarabine/daunorubicin had a significant efficacy in patients with AML, chronic myeloid leukemia (CML) or high-risk myelodysplastic syndromes. Glasdegib combined with low-dose cytarabine (LDAC) is a potential option for AML patients who are not suitable for intensive chemotherapy. Other selective SMO inhibitors, including taladegib (LY2940680) and saridegib (IPI-926), have also entered clinical trials for other cancers. As single-target agents, these SMO inhibitors have drug resistance problems. To reduce this problem, some novel inhibitors of terminal components of Hh signaling pathway are being developed, such as arsenic trioxide (ATO) and GANT-61.
The Wnt signaling pathway is associated with tumor development in breast cancer, ovarian cancer, esophageal squamous cell cancer, colon cancer, prostate cancer, and lung cancer. Until now, several drugs aimed at the Wnt signaling pathway have been in clinical trials, while the majority of Wnt inhibitors are in preclinical testing. Clinical data from initial trials have shown that ipafricept (OMP-54f28/FZD8-Fc) is a first-in-class recombinant fusion protein that antagonizes Wnt signaling. However, its role in patients with desmoid cancers and germ cell cancers is negligible. NCT02050178, ipafricept combined with ab-paclitaxel and gemcitabine in patients with untreated stage IV pancreatic cancer, NCT02092363, ipafricept combined with paclitaxel and carboplatin in patients with recurrent platinum-sensitive ovarian cancer, and NCT02069145, ipafricept combined with sorafenib in patients with HCC, are currently being investigated. PRI-724, a beta-catenin inhibitor, inhibits the interaction between beta-catenin and its transcriptional coactivators. Safety and efficacy testing of PRI-724 for patients with advanced myeloid malignancies (NCT01606579) and advanced or metastatic pancreatic cancer (NCT01764477) have been completed in phase I studies. CWP232291, another inhibitor of beta-catenin activity, has also been shown to be effective for AML (NCT03055286) in a phase I clinical study and for recurrent or refractory myeloma (NCT02426723) in a phase I/II clinical study. Other Wnt signaling inhibitors have also been under clinical trial, including LGK974 (NCT02278133), ETC-159 (NCT02521844), and OMP-18R5 (NCT01973309, NCT01957007, and NCT02005315).
Table 3 caption: Agents targeting CSC-associated signaling pathways and microenvironment in ongoing clinical trials
Table 3 data: Drug name Target Condition Phase Sample size NCT number Current status Hedgehog inhibitors Vismodegib (GDC-0449) Smoothened Recurrent or refractory medulloblastoma II 31 NCT00939484 Completed, has results Basal cell carcinoma 28 NCT01700049 Completed, has results Sarcoma 78 NCT01700049 Completed, has results Recurrent small-cell lung carcinoma 168 NCT01700049 Completed, has results Metastatic pancreatic cancer 98 NCT01088815 Completed, has results Ovarian cancer 104 NCT00739661 Completed, has results Metastatic colorectal cancer 199 NCT00636610 Completed, has results Sonidegib (LDE225) Basal cell carcinoma II 10 NCT01350115 Completed, has results Relapsed medulloblastoma 20 NCT01708174 Completed, has results Acute myeloid leukemia 70 NCT01826214 Completed, has results Pancreatic adenocarcinoma 20 NCT01431794 Completed, has results Advanced or metastatic hepatocellular carcinoma 9 NCT02151864 Completed Recurrent plasma cell myeloma 28 NCT02086552 Active, not recruiting, has results Advanced pancreatic cancer 39 NCT01485744 Active, not recruiting Advanced breast cancer I 12 NCT02027376 Completed, has results Glasdegib Acute myeloid leukemia II 255 NCT01546038 Completed, has results BMS-833923 (XL139) Solid tumors II 12 NCT01413906 Completed Small-cell lung carcinoma 5 NCT00927875 Completed Metastatic gastric, gastroesophageal, esophageal adenocarcinomas 39 NCT00909402 Completed Advanced or metastatic basal cell carcinoma 53 NCT00670189 Completed Leukemia 70 NCT01357655 Terminated, has results Taladegib (LY2940680) Localized esophageal or gastroesophageal junction cancer II 9 NCT02530437 Active, not recruiting Small-cell lung carcinoma 26 NCT01722292 Terminated, has results LEQ-506 Solid tumors I 57 NCT01106508 Completed G-024856 BCC I Patidegib (IPI-926) Basal cell carcinomas II 36 NCT02828111 Completed, has results Metastatic or locally advanced chondrosarcoma 105 NCT01310816 Completed Metastatic pancreatic cancer 122 NCT01130142 Completed Recurrent head and neck cancer I 9 NCT01255800 Completed Notch inhibitors MK-0752 gamma-Secretase Advanced breast cancer I 103 NCT00106145 Completed Pancreatic cancer I 44 NCT01098344 Completed Metastatic breast cancer I/II 30 NCT00645333 Completed, has results RO4929097 Recurrent melanoma II 14 NCT01196416 Completed, has results Advanced or metastatic sarcoma 78 NCT01154452 Completed, has results Recurrent renal cell carcinoma 12 NCT01141569 Completed, has results Advanced solid tumors 20 NCT01131234 Completed Recurrent and/or metastatic epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer 45 NCT01175343 Completed, has results Metastatic pancreas cancer 18 NCT01232829 Completed, has results Recurrent colon cancer 37 NCT01116687 Completed, has results Recurrent or refractory non-small-cell lung cancer 7 NCT01070927 Completed Nirogacestat (PF-03084014) Metastatic cancer pancreas II 3 NCT02109445 Terminated, has results Fibromatosis II 17 NCT01981551 Active, not recruiting Triple-negative breast neoplasms II 19 NCT02299635 Terminated, has results LY900009 Advanced cancer I 35 NCT01158404 Completed, has results Crenigacestat (LY3039478) Pan-Notch Advanced solid tumor I 12 NCT02836600 Active, not recruiting T cell acute lymphoblastic leukemia, T cell lymphoblastic lymphoma I/II 36 NCT02518113 Completed, has results AL101 Adenoid cystic carcinoma II 36 NCT03691207 Recruiting CB-103 Advanced or metastatic solid tumors and hematological malignancies I/II 165 NCT03422679 Recruiting BMS-906024 Advanced or metastatic solid tumors I 94 NCT01292655 Completed Lymphoblastic leukemia, acute T cell I 31 NCT01363817 Completed Demcizumab (OMP-21M18) DLL4 Pancreatic cancer II 207 NCT02289898 Completed, has results Non-squamous, non-small-cell neoplasm of lung II 82 NCT02259582 Completed, has results Brontictuzumab (OMP-52M51) Adenoid cystic carcinoma Not applicable 1 NCT02662608 Completed, has results Enoticumab (MEDI528) Advanced solid malignancies I 83 NCT00871559 Completed MEDI0639 Solid tumors I 58 NCT01577745 Completed, has results Wnt inhibitors Ipafricept (OMP-54F28) Wnt receptor Solid tumors I 26 NCT01608867 Completed Pancreatic cancer I 26 NCT02050178 Completed Ovarian cancer I 37 NCT02092363 Completed Hepatocellular cancer I 10 NCT02069145 Completed Vantictumab (OMP-18R5) Metastatic breast cancer I 37 NCT01973309 Completed Solid tumors I 35 NCT01345201 Completed Pancreatic cancer I 30 NCT02005315 Completed PRI-724 beta-Catenin/CBP Colorectal adenocarcinoma II 0 NCT02413853 Withdrawn Acute myeloid leukemia 49 NCT01606579 Completed Solid tumors 23 NCT01302405 Terminated Advanced pancreatic cancer 20 NCT01764477 Completed CWP232291 Acute myeloid leukemia I 69 NCT01398462 Completed Multiple myeloma I 25 NCT02426723 Completed LGK974 Porcupine Metastatic colorectal cancer I 20 NCT02278133 Completed Pancreatic cancer I 170 NCT01351103 Recruiting ETC-1922159 Solid tumors I 65 NCT02521844 Active, not recruiting Other signaling pathways inhibitors Galunisertib (LY2157299) TGF-beta Prostate cancer II 60 NCT02452008 Recruiting LY3200882 Colorectal cancer II 31 NCT04031872 Not yet recruiting AVID200 Malignant solid tumor I 36 NCT03834662 Recruiting Trabedersen (AP 12009) Pancreatic neoplasms II 62 NCT00844064 Completed Breast cancer 16 NCT01959490 Completed, has results Glioblastoma 141 NCT00431561 Completed Fresolimumab (GC1008) Non-small-cell lung carcinoma II 60 NCT02581787 Recruiting Metastatic Breast Cancer 23 NCT01401062 Completed, has results CarcinomaRenal cellMelanoma 29 NCT00356460 Completed Vactosertib (TEW-7197) Advanced-stage solid tumors I 35 NCT02160106 Completed NIS793 Breast cancerLung cancerHepatocellular cancer I 220 NCT02947165 Recruiting Ruxolitinib JAK Metastatic breast cancer III 29 NCT01594216 Completed Myeloproliferative neoplasms 309 NCT00952289 Completed, has results AZD4205 Advanced non-small-cell lung cancer II 120 NCT03450330 Recruiting SAR302503 Hematopoietic neoplasm II 97 NCT01523171 Completed SB1518 JAK/FLT3 Acute myelogenous leukemia II 76 NCT00719836 Completed PI3K inhibitors Alpelisib PI3K Advanced breast cancer II 90 NCT03386162 Recruiting Buparlisib (BKM120) Triple-negative metastatic breast cancer II 50 NCT01629615 Completed BYL719 Advanced or metastatic gastric cancer I 18 NCT01613950 Completed SF1126 Advanced or metastatic solid tumors I 44 NCT00907205 Completed SAR245409 PI3K and mTOR Advanced or metastatic solid tumors I 146 NCT01390818 Completed, has results EGFR inhibitors Bevacizumab EGFR Breast cancer I 75 NCT01190345 Completed Matuzumab (EMD 72000) Esophageal cancer II 72 NCT00215644 Completed, has results Non-small-cell lung carcinoma 150 NCT00111839 Completed, has results Metabolism inhibitors Venetoclax (ABT-199) BCL-2 Acute myelogenous leukemia II 32 NCT01994837 Completed, has results Pegzilarginase Recombinant pegylated arginase Small-cell lung cancer II 84 NCT03371979 Active, not recruiting 131I-TLX-101 LAT1 Glioblastoma multiforme II 44 NCT03849105 Recruiting Rifampicin FAS Advanced solid tumors I 36 NCT03077607 Completed, has results TVB-2640 Advanced breast cancer II 80 NCT03179904 Recruiting IM156 AMPK Advanced solid tumor I 36 NCT03272256 Recruiting Telaglenastat Glutaminase Solid tumors II 85 NCT03965845 Recruiting CB-1158 Arginase Advanced solid tumors II 5 NCT03361228 Completed Niche inhibitors Plerixafor (Mozobil) CXCR4 Advanced pancreatic, ovarian, and colorectal cancers I 26 NCT02179970 Completed BL-8040 Metastatic pancreatic adenocarcinoma II 23 NCT02907099 Active, not recruiting BKT140 Multiple myeloma II 16 NCT01010880 Completed BMS-936564 Relapsed/refractory multiple myeloma I 46 NCT01359657 Completed BMS-936564 Acute myelogenous leukemia I 98 NCT01120457 Completed LY2510924 Solid tumor I 9 NCT02737072 Terminated, has results MSX-122 Refractory metastatic or locally advanced solid tumors I 27 NCT00591682 Suspended USL311 Advanced solid tumors and relapsed/recurrent Glioblastoma multiforme II 120 NCT02765165 Recruiting AMD3100 Acute myeloid leukemia II 52 NCT00512252 Completed, has results Reparixin CXCR1/2 Breast cancer II 20 NCT01861054 Terminated Defactinib (VS-6063) FAK Non-small-cell lung cancer II 55 NCT01951690 Completed
In addition, the mitochondrial glycolysis pathway also plays a key role in regulating the proliferation and apoptosis of CSCs. Venetoclax, a BCL-2 inhibitor, was initially approved by the FDA recently and shows good tolerance and activity for AML patients with adverse reactions. Two arachidonate 5-lipoxygenase inhibitors, VIA-2291 and GSK2190915, might be potent agents for targeting LSCs in CML, as shown in Table 3.
Other abnormal signaling pathways have also been found in CSCs, such as TGF-beta, JAK-STAT, PI3K, and NF-kappaB. These signaling pathways are not independent of each other but rather form a complex signaling network. Agents targeting CSC-associated signaling pathways in ongoing clinical trials are listed in Table 3.
