Investigational Drug Treatments for Triple-Negative Breast Cancer
Abstract
:1. Introduction
2. Material and Methods
3. Results
3.1. PI3K/AKT/mTOR Pathway
3.2. PARP Inhibitors
3.3. Aurora Kinase Inhibitors
3.4. Histone Deacetylase Inhibitors
3.5. Other Inhibitors
3.6. Immunotherapy
4. Discussion
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Conflicts of Interest
References
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Study | Sample Source | Therapy | Pathway/Mechanism of Action | Results | ||
---|---|---|---|---|---|---|
1 | Ganesan et al., 2014 [25] | Phase I trial. | 106 (98 evaluated) consecutive patients with advanced or metastatic TNBC. | Chemotherapy only (n = 8), combination chemotherapy and targeted therapy (n = 62), single-agent targeted therapy (n = 16), and targeted therapy with 2 or more agents (n = 20). | PI3K/AKT/mTOR. | Treatment with anti-angiogenic factors and/or PI3K/AKT/mTOR inhibitors demonstrated prolonged free survival in patients with metastatic TNBC respectively (p = 0.023 and p = 0.018). |
2 | Huck et al., 2014 [57] | In vivo study in immunocompromised mice-followed by clinical study. | In vivo models of TNBC grown in immune compromised mice. | 60 and 80 mg/m2 of paclitaxel (every week), MLN8237 twice a day. | Aurora kinase inhibitor. | The highest dose of MLN8237 and paclitaxel offer the best efficacy. |
3 | Llombart-Cussacet al., 2015 [39] | Phase II trial. | 141 patients with TNBC Stage II-IIIa. | Praclitaxel (80 mg/m2, n = 47) alone or in combination with iniparib, either once weekly (11.2 mg/kg, n = 46) or twice weekly (5.6 mg/kg, n = 48) for 12 weeks. | PARP inhibitor. | Best overall response in the breast (60, 61 and 63%) and breast conservation rate (53, 54 and 50%). Addition of iniparib to weekly praclitaxel did not add relevant antitumor activity or toxicity. |
4 | Min et al., 2015 [65] | In vitro and in vivo studies. | TNBC cell lines, xenografts models. | SAHA in combination with olaparib. | HDACIs and PARP inhibitors. | Down-regulation of the proliferative signaling pathway, increased apoptotic and autophagic cell death, and accumulation of DNA damage. |
5 | Arango et al., 2015 [75] | In vitro and in vivo cell lines. | 26 TNBC patient-derived xenografts (PDXs). | Selinexor was combined with paclitaxel, carboplatin, eribulin, gemcitabine and doxorubicin. | Nucleo-cytoplasmatic transport inhibitor. | Selinexor as a single agent reduced tumor growth in vivo in 4 of 5 different TNBCPDX models, with a median tumor growth inhibition ratio of 42% and demonstrated greater antitumor efficacy in combination with paclitaxel or eribulin. |
6 | Mitri et al., 2015 [81] | Phase I study. | 9 patients with TNBC. | Escalating doses of dinaciclib given on day 1 followed by standard dose of epirubicin given on day 2 of a 21-day cycle. | Cyclin dependent kinase inhibitor. | Dose escalation did not proceed past the second cohort due to toxicity. The first dose level was also found to be too toxic. No treatment responses were noted, median time to progression was 5.5 weeks. |
7 | Tolaney et al., 2015 [83] | Phase II study. | 22 patients with TNBC. | Twice daily oral dosing of tivantinib (360 mg po bid) during a 21-day cycle. | Tyrosine kinase inhibitor. | The overall response rate was 5% (95% CI 0–25%) and the 6-month PFS was 5% (95% CI 0–25%), with 1 patient achieving a partial response. |
8 | Basho et al., 2016 [26] | Phase I trial. | 52 women with metaplastic TNBC. | Liposomal doxorubicin, bevacizumab and temsirolimus (DAT) (n = 39) or liposomal doxorubicin, bevacizumab, and everolimus (DAE) (n = 13). | PI3K/AKT/mTOR. | The response rate was 21% (complete response = 4, 8%, partial response = 7, 13%) and 19% of patients had stable disease for at least 6 months, for a clinical benefit rate of 40%. |
9 | Kummar et al., 2016 [41] | Phase II study. | 45 adult patients with TNBC. | Oral cyclophosphamide 50 mg once daily with or without oral veliparib at 60 mg daily in 21-day cycles. | PARP inhibitors. | Response rates and median PFS did not significantly differ between the 2 groups. The addition of veliparib to cyclophosphamide, did not improve the response rate. |
10 | Pham et al., 2016 [86] | In vivo preclinical study with xenografts. | Preclinical mouse models of orthotopic primary TNBC xenografts. | Bevacizumab and CRLX101. | Anti-VEGF. | CRLX101 showed antitumor efficacy, reduced metastasis, and prolonged survival. |
11 | Brinkman et al., 2016 [91] | In vivo study in mice. | Human TNBC cell lines. | Aminoflavone 7 mg/kg intravenously every 4 days. | Anti-EGFR. | Aminoflavone demonstrated antitumor efficacy against EGFR- over-expressing TNBC. |
12 | Nanda et al., 2016 [108] | Phase I clinical trial. | 111 patients with TNBC. | Pembrolizumab given intravenously at 10 mg/kg every 2 weeks. | Anti-PD-1. | The overall response rate was 18.5%, the median time to response was 17.9 weeks and the median duration of response was not reached. |
13 | Evans et al., 2017 [42] | Normal and tumor DNA sequencing, RNASeq, and reverse phase protein arrays (RPPA), immunohistochemistry and in vivo treatment in BC patient derived xenografts. | 26 patient-derived xenografts, obtained from surgical samples of recurrent tumors from 25 patients. | Use of chemotherapy with trametinib, buparlisib and/or talazoparib. | PARP inhibitor. | Talazoparib caused dramatic regression in 5 of 12 PDXs. 4 of 5 talazoparib-sensitive models did not harbor germline BRCA1/mutations, but several had somatic alterations in homologous repair pathways, including ATM deletion and BRCA2 alterations. |
14 | Wali et al., 2017 [92] | Clinical study. | TNBC cell lines. | 128 investigational drugs as either single agents or in 768 pairwise drug combinations. | ROS1 inhibitor. | The ABT-263/crizotinib combination offers a rapid path to clinic demonstrated RTK blockade, inhibition of mitogenic signaling and pro-apoptotic signal induction in basal and mesenchymal stem-like TNBC. |
15 | Tolaney et al., 2017 [109] | Phase II study. | 35 patients with TNBC. | Cabozantinib (60 mg daily) on a 3-week cycle and were restaged after 6 weeks and then every 9 weeks. | Tyrosine kinase inhibitor. | 3 patients achieved a partial response, 9 patients achieved stable disease for at least 15 weeks, and thus the clinical benefit rate was 34%/Median PFS was 2 months. 2 patients had TNBC with MET amplification. |
16 | Basho et al., 2018 [27] | Phase I trial. | 43 patients with non-metaplastic TNBC and 59 patients with advanced metaplastic BC. | mTOR inhibition weekly (temsirolimus or everolimus) with liposomal doxorubicin and bevacizumab every 3 weeks (DAT/DAE). | PI3K/AKT/mTOR inhibition and anti-VEGF. | Median PFS for the non-metaplastic TNBC and MpBC patients was 2.5 months and 4.8 months, respectively. Median OS for the non-metaplastic TNBC and MpBC patients was 3.7 months and 10 months, respectively. DAT/DAE appeared to be more effective in MpBC compared with non-metaplastic TNBC. |
17 | Carducci et al., 2018 [58] | In-human trial included dose-escalation and dose-expansion phases. | Patients with 3 tumor types: taxane- and platinum-resistant ovarian cancer, taxane-resistant TNBC, and castration-resistant and taxane- or cisplatin/etoposide resistant prostate cancer. | AMG 900 for 4 days on/10 days off at 1–50 mg/day. | Aurora kinase inhibitors. | 3 of 29 (10.3%, 95% CI:2.0–28.0%) patients with ovarian cancer showed partial response. median duration of response was 24.1 weeks (95% CI: 16.1–34.1). 7 patients (24.1%, 95% CI:10.3–43.5%) experienced partial response. 5/9 patients positive for p53 expression responded to treatment. No objective responses were observed in patients with TNBC or CRPC. |
18 | Ono et al., 2018 [66] | Flow cytometry analysis. | TNBC cell lines. | OBP-801 or OBP-801 in combination with eribulin. | HDACIs. | Suppression of Bcl-xL and the MAPK pathway. |
19 | Song et al., 2018 [67] | MTT dye reduction method. | TNBC cell lines HCC1806 and HCC38. | Trichostatin A (TSA) or TSA in combination with doxorubicin. | HDACIs. | Decreased expression of CYCLIN D1, CDK4, CDK6 and BCL-XL, but increased P21 expression and inhibition of the proliferation of HCC1806 and HCC38 cells. |
20 | Rinnerthaler et al., 2018 [94] | Phase I and II clinical trials. | Patients with metastatic TNBC, already treated with at least 1 prior line of chemotherapy. | Ixazomib in combination with carboplatin on days 1, 8, and 15 in a 28-day cycle. The phase I part of this study utilizes an alternate dose escalation accelerated titration design. After establishing the maximum tolerated dose, the combination will be further evaluated (phase II, including 41 evaluable patients). | Proteasome inhibitor. | The results will be recorded in the future. |
21 | Schmid et al., 2018 [110] | Phase III trial. | 451 patients with untreated metastatic TNBC. | Atezolizumab plus nab-paclitaxel or placebo plus nab-paclitaxel. | Anti-PD-L1. | The median overall survival was 21.3 months with atezolizumab plus nab-paclitaxel and 17.6 months with placebo plus nab-paclitaxel. Among patients with PD-L1-positive tumors, the median overall survival was 25 months and 15.5 months, respectively. |
22 | Bernier et al., 2018 [111] | In vivo study. | Mice with TNBC | CTLA-4 inhibitor and DZ- 2384 co-administration. | CTLA-4 inhibition. | CTLA-4 immunotherapy exerted synergistic action with DZ- 2384. In preclinical models, this combination was superior and with less side-effects, comparing to CTLA-4 immunotherapy and taxanes. |
23 | Santa-maria et al., 2018 [112] | Pilot study | 18 patients with advanced estrogen receptor positive BC or TNBC | Durvalumab and tremelimumab. | PD-1/PD-L1/CTLA-4 inhibition. | This combination was more effective in patients with TNBC, as it increased cytotoxicity of T-cells and lead to clonal T-cell expression. Responses were made only in patients with TNBC (ORR = 43%), who had higher mutational gene expression and up-regulation of perforin 1 and CD8. |
24 | Lee et al., 2019 [28] | Phase I trial. | Patients with metastatic TNBC. | Everolimus and eribulin in different dosages combination in 25 patients. | PI3K/AKT/mTOR inhibition. | Among the 25 patients, 9 were stable, 9 reported partial response and 7 had progressive disease. Toxicity due to chemotherapy included hematological disorders, fatigue, stomatitis and hyperglycemia. |
25 | Maiti et al., 2019 [68] | Sphere formation assay. | TNBC cell lines. | Entinostat. | HDACIs. | Re-expression of the anti-angiogenic genes, serpin family F member 1 (SERPINF1) and thrombospondin 2 (THBS2), and to that of the tumor suppressor genes, phosphatase and tensin homolog (PTEN) and p21, and reduced VM structures. Down-regulation of the expression of vascular endothelial growth factor A (VEGF-A), and that of the epithelial-mesenchymal transition (EMT)-related genes, Vimentin and β-catenin. |
26 | Park et al., 2019 [98] | In vivo study. | A xenograft model of AR expressing TNBC in mouse models. | BET inhibitor JQ1. | BET inhibitor. | JQ1 showed significant anti-tumor activity in vivo in TNBC xenograft mouse models as a monotherapy and in combination with anti-AR therapy. |
27 | Cortés et al., 2019 [113] | Phase III trial. | Patients with PD-L1-positive tumors. | Atezolizumab 1200 mg or placebo every 3 weeks with the chosen chemotherapy. | Anti-PD-L1. | Unacceptable toxicity or withdrawal. |
28 | Voorwerk et al., 2019 [114] | Phase II trial. | 67 patients with TNBC. | Nivolumab only or radiation or cyclphosphamide or cisplatin or doxorubicin all followed by nivolumab. | Anti-PD-1. | The most effective responses were done in the doxorubicin and cisplatin groups with ORR 35% and 23% respectively. After the use of this chemotherapeutic regimens, up-regulation of PD-L1 pathway and increase in inflammation and T-cell cytotoxicity occurred. Thus, the administration of these drugs before immunotherapy might enhance its action. |
29 | Owusu-Brackett et al., 2020 [29] | In vitro cell viability assay. | TNBC cell lines. | AZD8186 in combination with paclitaxel, eribulin. | PI3K/AKT/mTOR inhibition. | AZD8186 had single agent efficacy in PTEN-deficient TNBC cell lines in vitro but had limited single agent efficacy in vivo. AZD8186 had enhanced efficacy when combined with paclitaxel and anti-PD1 in vivo. |
30 | Pothuri et al.,2020 [43] | Clinical trial. | 44 patients with ovarian or TNBC. | Veliparib and doxorubicin in various dosages. | PARP inhibitor. | Although complete clinical response was observed in two cases, and the anti-tumor efficacy was generally acceptable, complications such as oral squamous cell carcinomas appeared. |
31 | Tolcher et al.,2020 [59] | Clinical trial. | 126 patients with TNBC or melanoma. | Trametinib and uprosertib in various dosages. | Aurora kinase inhibitors. | The anti-tumor efficacy was minimal, whereas adverse effects such as severe diarrheas or rashes appeared. |
32 | Milazzo et al., 2020 [69] | In vitro and in vivo studies. | TNBC cell lines, xenografts models. | ST8176AA1 (ADC). | HDACIs. | Higher anti-tumor activity of ST8176AA1 compared to trastuzumab, increased expression of ErbB2 and estrogen receptor in TNBC cells, lower expression of the proliferation marker Ki67 and higher expression of cleaved caspase-3 in mice treated with the ADC compared to those treated with trastuzumab. |
33 | Sardesai et al., 2020 [102] | Phase I study. | Patients with TNBC. | Carboplatin on day 1, weekly paclitaxel at 80 mg and RO4929097 10 mg daily given orally on days 1–3, 8–10 and 15–17 for 6 21-day cycles. RO4929097 was escalated in 10 mg using the 3 + 3 dose escalation design. | γ-secretase inhibitor. | RO4929097 at 10 mg would have been the likely dose level for further development. |
34 | Ma et al., 2021 [30] | In vitro study. | MDA-MB-231, A549 and HeLa cell lines. | Anilide. | PI3K/AKT/mTOR inhibition. | Anilide enhance apoptosis and inhibit the migration and the proliferation of TNBC cells. |
35 | Eikesdal et al., 2021 [44] | Clinical trial. | 32 patients with TNBC, who have not received previously chemotherapy. | Olaparib. | PARP inhibitor. | Olaparib is effective against treatment-naïve TNBC cells with HR deficiency. |
36 | Brufsky et al.,2021 [103] | Phase II clinical trial. | Patients with locally advanced or metastatic TNBC. | Cobimetinib plus chemotherapy, with or without atezolizumab. | MAPK inhibition. | No increase in survival was noticed in any regimen. |
37 | Winer et al., 2021 [115] | Clinical trial. | 1098 patients with metastatic TNBC. | Pembrolizumab versus chemotherapy. | Anti-PD-1. | Pembrolizumab did not increase survival rates. |
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Damaskos, C.; Garmpis, N.; Garmpi, A.; Nikolettos, K.; Sarantis, P.; Georgakopoulou, V.E.; Nonni, A.; Schizas, D.; Antoniou, E.A.; Karamouzis, M.V.; et al. Investigational Drug Treatments for Triple-Negative Breast Cancer. J. Pers. Med. 2021, 11, 652. https://doi.org/10.3390/jpm11070652
Damaskos C, Garmpis N, Garmpi A, Nikolettos K, Sarantis P, Georgakopoulou VE, Nonni A, Schizas D, Antoniou EA, Karamouzis MV, et al. Investigational Drug Treatments for Triple-Negative Breast Cancer. Journal of Personalized Medicine. 2021; 11(7):652. https://doi.org/10.3390/jpm11070652
Chicago/Turabian StyleDamaskos, Christos, Nikolaos Garmpis, Anna Garmpi, Konstantinos Nikolettos, Panagiotis Sarantis, Vasiliki E. Georgakopoulou, Afroditi Nonni, Dimitrios Schizas, Efstathios A. Antoniou, Michalis V. Karamouzis, and et al. 2021. "Investigational Drug Treatments for Triple-Negative Breast Cancer" Journal of Personalized Medicine 11, no. 7: 652. https://doi.org/10.3390/jpm11070652