miR-34a-Mediated Survivin Inhibition Improves the Antitumor Activity of Selinexor in Triple-Negative Breast Cancer.

Published on May 29, 2021in Pharmaceuticals, policy and law
· DOI :10.3390/PH14060523
Silvia Martini3
Estimated H-index: 3
,
Valentina Zuco25
Estimated H-index: 25
+ 7 AuthorsNadia Zaffaroni66
Estimated H-index: 66
Source
Abstract
Triple-negative breast cancer (TNBC) is an aggressive disease with limited therapeutic options. Here, we pursued a combinatorial therapeutic approach to enhance the activity of selinexor, the first-in-class XPO1 inhibitor, by miR-34a ectopic expression in human TNBC experimental models. Anti-proliferative activity induced by selinexor and miR-34a expression, singly and in combination, was evaluated by MTS assay and cell counting. The effect of treatments on survivin and apoptosis-related proteins was assessed by western blotting and ELISA. The antitumor and toxic effects of individual and combined treatments were evaluated on TNBC orthotopic xenografts in SCID mice. Selinexor consistently showed anti-proliferative activity, although to a variable extent, in the different TNBC cell lines and caused the impairment of survivin expression and intracellular distribution, accompanied by apoptosis induction. Consistent with in vitro data, the XPO1 inhibitor variably affected the growth of TNBC orthotopic xenografts. miR-34a cooperated with selinexor to reduce survivin expression and improved its anti-proliferative activity in TNBC cells. Most importantly, miR-34a expression markedly enhanced selinexor antitumor activity in the less sensitive TNBC xenograft model, in absence of toxicity. Our data form a solid foundation for promoting the use of a miR-34a-based approach to improve the therapeutic efficacy of selinexor in TNBC patients.
References0
Newest
#1Asfar S. Azmi (WSU: Wayne State University)H-Index: 59
#2Mohammed Hafiz Uddin (WSU: Wayne State University)H-Index: 2
Last. Ramzi M. Mohammad (WSU: Wayne State University)H-Index: 60
view all 3 authors...
Exportin 1 (XPO1), also known as chromosome region maintenance protein 1, plays a crucial role in maintaining cellular homeostasis via the regulated export of a range of cargoes, including proteins and several classes of RNAs, from the nucleus to the cytoplasm. Dysregulation of this protein plays a pivotal role in the development of various solid and haematological malignancies. Furthermore, XPO1 is associated with resistance to several standard-of-care therapies, including chemotherapies and ta...
3 CitationsSource
#1Megan N. Dang (UD: University of Delaware)H-Index: 4
#2Carolina Gomez Casas (UD: University of Delaware)
Last. Emily S. Day (UD: University of Delaware)H-Index: 21
view all 3 authors...
Triple-negative breast cancer (TNBC) is an aggressive disease that requires new interventions. A promising approach to improve patient prognosis is to introduce tumor suppressive miR-34a into TNBC cells. Unfortunately, naked miR-34a is not effective therapeutically because it is degraded by nucleases and cannot passively enter cells. Nanocarriers designed to increase miR-34a stability and cellular entry have lacked specificity and potency. To overcome these limitations, we conjugated miR-34a to ...
Source
#1Silvia MartiniH-Index: 3
#2Mariangela FiginiH-Index: 26
Last. Alessandro SattaH-Index: 4
view all 12 authors...
Triple-negative breast cancer (TNBC) is an aggressive disease with poor prognosis and limited therapeutic options. Recent advances in the immunotherapy field have enabled the development of new treatment strategies, among which the use of bispecific antibodies (BsAbs), able to redirect T cells against tumors, has shown promising results. In particular, a BsAb that uses TNF-related apoptosis-inducing ligand receptor 2 (TRAIL-R2) as a target was constructed and demonstrated good results in redirec...
2 CitationsSource
#1David S. Hong (University of Texas MD Anderson Cancer Center)H-Index: 79
#2Yoon-Koo Kang (UOU: University of Ulsan)H-Index: 77
Last. Muhammad Shaalan Beg (UTSW: University of Texas Southwestern Medical Center)H-Index: 19
view all 23 authors...
In this first-in-human, Phase 1 study of a microRNA-based cancer therapy, the recommended Phase 2 dose (RP2D) of MRX34, a liposomal mimic of microRNA-34a (miR-34a), was determined and evaluated in patients with advanced solid tumours. Adults with various solid tumours refractory to standard treatments were enrolled in 3 + 3 dose-escalation cohorts and, following RP2D determination, expansion cohorts. MRX34, with oral dexamethasone premedication, was given intravenously daily for 5 days in 3-week...
76 CitationsSource
#1Chintan H. Kapadia (UD: University of Delaware)H-Index: 7
#2Stephen A. Ioele (UD: University of Delaware)H-Index: 3
Last. Emily S. Day (UD: University of Delaware)H-Index: 21
view all 3 authors...
Triple-negative breast cancer (TNBC) accounts for 15-25% of diagnosed breast cancers, and its lack of a clinically defined therapeutic target has caused patients to suffer from earlier relapse and higher mortality rates than patients with other breast cancer subtypes. MicroRNAs (miRNAs) are small non-coding RNAs that regulate the expression of multiple genes through RNA interference to maintain normal tissue function. The tumor suppressor miR-34a is downregulated in TNBC, and its loss-of-express...
7 CitationsSource
#1Yahiya Y. Syed (Springer Science+Business Media)H-Index: 17
Selinexor (XPOVIO™) is a first-in-class, oral, small molecule Exportin-1 (XPO1) inhibitor that is being developed by Karyopharm Therapeutics for the treatment of cancer. Selinexor (in combination with dexamethasone) received accelerated approval in the USA in July 2019 for the treatment of adult patients with relapsed or refractory multiple myeloma (RRMM). Selinexor is also undergoing clinical development in a wide range of haematological and solid cancers. This article summarizes the milestones...
30 CitationsSource
#2Roohi Ismail-KhanH-Index: 19
Last. Hyo S. HanH-Index: 15
view all 10 authors...
LESSONS LEARNED: Single-agent selinexor has limited activity in heavily pretreated patients with metastatic triple-negative breast cancer.Selinexor 60 mg by mouth twice weekly was generally well tolerated with a side-effect profile consistent with previous clinical trials.Future studies of selinexor in this population should focus on combination approaches and a biomarker-driven strategy to identify patients most likely to benefit. BACKGROUND: This phase II trial evaluated the safety, pharmacody...
8 CitationsSource
#1Lu Zhang (Chongqing University)H-Index: 1
#2Yi Liao (Third Military Medical University)H-Index: 5
Last. Liling Tang (Chongqing University)H-Index: 2
view all 3 authors...
MicroRNA-34 (miR-34) has been reported to be dysregulated in various human cancers and regarded as a tumor suppressive microRNA because of its synergistic effect with the well-known tumor suppressor p53. Along with the application of MRX34, the first tumor-targeted microRNA drug which based on miR-34a mimics, on phase I clinical trial (NCT01829971), the significance of miR-34 is increasingly recognized. miR-34 plays a crucial role on repressing tumor progression by involving in epithelial-mesenc...
83 CitationsSource
#1Paola Bonetti (IIT: Istituto Italiano di Tecnologia)H-Index: 11
#2Montserrat Climent (IIT: Istituto Italiano di Tecnologia)H-Index: 5
Last. Francesco Nicassio (IIT: Istituto Italiano di Tecnologia)H-Index: 21
view all 9 authors...
The role of the tumour-suppressor miR-34 family in breast physiology and in mammary stem cells (MaSCs) is largely unknown. Here, we revealed that miR-34 family, and miR-34a in particular, is implicated in mammary epithelium homoeostasis. Expression of miR-34a occurs upon luminal commitment and differentiation and serves to inhibit the expansion of the pool of MaSCs and early progenitor cells, likely in a p53-independent fashion. Mutant mice (miR34-KO) and loss-of-function approaches revealed two...
21 CitationsSource
#1Alessandro SattaH-Index: 4
#2Giulia GraziaH-Index: 10
Last. Mariangela FiginiH-Index: 26
view all 11 authors...
T-cell-based immunotherapy strategies have profoundly improved the clinical management of several solid tumors and hematological malignancies. A recently developed and promising immunotherapy approach is to redirect polyclonal MHC-unrestricted T lymphocytes towards cancer cells by bispecific antibodies (bsAbs) that engage the CD3 complex and a tumor-associated antigen (TAA). The TNF-related apoptosis-inducing ligand receptor 2 (TRAIL-R2) is an attractive immunotherapy target, frequently expresse...
4 CitationsSource
Cited By0
Newest