Table 2 Therapeutic strategies of targeting tumor-intrinsic signaling in preclinical studies and clinical trials
Target | Therapeutic agent | Phase | Tumor type | Effect | Trial number | Ref |
|---|---|---|---|---|---|---|
BRAF | Vemurafenib | III | BRAF(V600) mutation-positive melanoma | Well tolerated | NCT01667419 | 92 |
BRAF/MEK | Vemurafenib + cobimetinib | Ib | Advanced BRAF-mutated melanoma | Safe and tolerable | NCT01271803 | 93 |
Vemurafenib + cobimetinib | III | Advanced BRAFV600-mutant melanoma | Improved progression-free survival, increased toxicity | NCT01689519 | 94, 95 | |
Dabrafenib + trametinib | III | BRAFV600-mutant metastatic melanoma | Durable (≥ 3 years) survival is achievable | NCT01584648 | 96 | |
Dabrafenib + trametinib | III | BRAFV600-mutant unresectable or metastatic melanoma | Survival advantage | NCT01597908 | 97 | |
Dabrafenib + trametinib | III | Metastatic melanoma with BRAFV600 mutation | Improved overall survival | NCT01597908 | 98 | |
Dabrafenib + trametinib | III | Melanoma with BRAFV600 mutation | Significantly lower risk of recurrence | NCT01682083 | 99 | |
Dabrafenib + trametinib | II | Untreated BRAFV600-mutant non-small cell lung cancer | Meaningful antitumor activity, manageable safety profile | NCT01336634 | 100, 101 | |
Dabrafenib + trametinib | II | BRAF-mutant melanoma | Longer progression-free survival and duration of response with a higher rate of grade 3/4 adverse events | NCT02130466 | 102 | |
MEK | Trametinib | II | Oral cavity squamous cell carcinoma | Clinical tumor responses | NCT01553851 | 103 |
IDO | Epacadostat | I | Advanced Solid Malignancies | Well tolerated, effectively normalized kynurenine levels | NCT01195311 | 105 |
Epacadostat | II | Advanced epithelial ovarian, primary peritoneal, or fallopian tube cancer | Well tolerated, no significant efficacy in ovarian cancer | NCT01685255 | 106 | |
Indoximod | I | Advanced solid tumors | Safe, best response was stable disease for > 6 months in 5 patients | NCT00567931 | 107 | |
Navoximod | Ia | Recurrent advanced solid tumors | Well tolerated, decreased kynurenine levels in plasma | NCT02048709 | 108 | |
Indoximod + docetaxel | I | Metastatic solid tumors | Well tolerated, no increase in toxicities or pharmacokinetic interactions | NCI #HHSN261201100100C | 110 | |
Indoximod + checkpoint inhibitors | II | Advanced melanoma | 52% overall response rate | NA | 109 | |
Navoximod + atezolizumab | I | Advanced cancers | Acceptable safety and tolerability | NCT02471846 | 111 | |
CTNNB1 (β-catenin) | NTRC 0066-0 | Xenograft model | CTNNB1 mutant cancers | Complete inhibition of tumor growth | NA | 112 |
STAT3 | Stattic + metformin | In vitro experiment | Brain cancer | Inhibited tumor initiating cells | NA | 115 |
Stattic + recombinant vaccinia virus VG9 | Xenograft model | Solid tumors | Superior antitumor ability | NA | 116 | |
PI3K | Duvelisib | I | Relapsed/refractory T cell lymphoma | Promising clinical activity and an acceptable safety profile | NCT01476657 | 117, 118 |
PI3K/mTOR | Dactolisib | In vitro and in vivo experiments | Glioblastomas | Antitumor activity | NA | 119 |
Omipalisib | In vitro experiment | Oncogenically transformed cells from neurocutaneous melanocytosis | Inhibited clonogenic growth | NA | 120 | |
Akt | Akti-1/2 | In vitro experiment | Breast cancer | An anticancer therapeutic strategy | NA | 121 |
NF-κB | QNZ | In vitro and in vivo experiment | Colorectal cancer | Decreased cell invasion and migration abilities as well as expression of metastasis-related markers | NA | 122 |
PDTC | In vitro and in vivo experiments | Multidrug-resistant breast cancer | Tumor growth inhibition | NA | 123 | |
SN50 | In vitro and in vivo experiments | Malignant brain tumor | Loss of oncogenesis, differentiation of stem-like cells | NA | 124 | |
TLR4 | Rapamycin | In vitro experiment | Colon cancer | Inhibited IL-6, PGE(2) production, and cell invasion | NA | 125 |