Bio-Synthesis, Inc. to supply peptide-BNA for the treatment of triple negative breast cancer
Cancer continues to pose a problem as approximately ~1500 are expected to die daily from cancer in the U.S. alone. Breast cancer is the leading type of cancer for women and is more common with higher survival rates in developed world. In addition to conventional therapies, treatments include hormone blocking therapy and targeted therapy, ex. trastuzumab inhibiting human epidermal growth factor receptor 2 (Her2) receptor. (Alvarez et al., 2010).
For therapy, breast cancers are often classified according to their ‘triple status’. Triple status refers to the expression level of human epidermal growth factor receptor 2 receptor (Her2), estrogen receptor (ER), and progesterone receptor (PR). Triple negative breast cancer lacks the expression of these receptors, undermining the efficacy of drugs targeting these receptors. Given their poor survivability, an urgent need exists to develop novel therapies.
Oncogenic signaling pathways driven by protein kinase B (AKT) or mitogen activated protein kinase (MAPK) play a critical role in regulating the growth of various human cancers including breast cancer (Samadi et al. 2018). The activity of these kinases is negatively regulated by phosphatases.
MicroRNAs (miRNAs) are small noncoding RNAs that regulate gene expression by targeting mRNAs for degradation or suppressing mRNA translation. The microRNA miR-21 was shown to be upregulated in human breast cancer cells (Iorio et al., 2005). As the targets of miR-21 include tumor suppressors phosphatase and tensin homolog (PTEN) (Meng et al., 2007) and human MutS protein homolog 2 (hMSH2) (Valeri et al, 2010), suppressing the activity of miR-21 represents an attractive approach for treating triple negative breast cancer.
A promising therapy is to devise an oligonucleotide-based blocking agent that hybridizes to miR-21 in the RNA-induced silencing complex (RISC) to free target mRNAs from degradation. The potency of the miR-21 blocker could be greatly improved by using aminomethyl bridged nucleic acid (BNA) as it allows better base-pair stacking and a high stability, elevates Tm, and lowers toxicity (Rahman et al 2007). Thus, the therapeutic efficacy of the miR-21 blocker could be increased through the BNA technology.
Bio-Synthesis, Inc. is uniquely poised to provide BNA as it has acquired a license from BNA Inc. of Osaka, Japan for the manufacturing and distribution of BNA-NC, a third generation of BNA oligonucleotides. Recently, Bio-Synthesis, Inc. has entered into collaborative agreement with Bind Therapeutics, Inc. to synthesize miR-21 blocker using BNA. To provide tumor selectivity, the miR-21 blocker will be conjugated to a peptide that allows selective uptake by breast cancer cells.
Alvarez RH, Valero V, Hortobagyi GN. Emerging targeted therapies for breast cancer. (2010). J Clin Oncol. 28:3366-79. PMID: 20530283 DOI: 10.1200/JCO.2009.25.4011
Iorio MV, Ferracin M, Liu CG, Veronese A, Spizzo R, Sabbioni S, Magri E, Pedriali M, Fabbri M, Campiglio M, Ménard S, Palazzo JP, Rosenberg A, Musiani P, Volinia S, Nenci I, Calin GA, Querzoli P, Negrini M, Croce CM. MicroRNA gene expression deregulation in human breast cancer. (2005) Cancer Res. 65:7065-70. PMID: 16103053 DOI: 10.1158/0008-5472.CAN-05-1783
Li S, Shen Y, Wang M, Yang J, Lv M, Li P, Chen Z, Yang J. Loss of PTEN expression in breast cancer: association with clinicopathological characteristics and prognosis. (2017) Oncotarget. 8:32043-32054. PMID: 28410191 PMCID: PMC5458267 DOI: 10.18632/oncotarget.16761
Meng F, Henson R, Wehbe-Janek H, Ghoshal K, Jacob ST, Patel T. MicroRNA-21 regulates expression of the PTEN tumor suppressor gene in human hepatocellular cancer. (2007) Gastroenterology. 133: 647–58. PMC 4285346. PMID 17681183 doi:10.1053/j.gastro.2007.05.022.
Rahman, S.M.; Seki, S.; Utsuki, K.; Obika, S.; Miyashita, K.; Imanishi, T. 2',4'-BNA(NC): a novel bridged nucleic acid analogue with excellent hybridizing and nuclease resistance profiles. (2007) Nucleosides Nucleotides Nucleic Acids 26, 1625-1628. PMID: 18066840 DOI: 10.1080/15257770701548980
Samadi P, Saki S, Dermani FK, Pourjafar M, Saidijam M. Emerging ways to treat breast cancer: will promises be met? (2018) Cell Oncol (Dordr). 41:605-621. PMID: 30259416 doi: 10.1007/s13402-018-0409-1.
Valeri N, Gasparini P, Braconi C, Paone A, Lovat F, Fabbri M, Sumani KM, Alder H, Amadori D, Patel T, Nuovo GJ, Fishel R, Croce CM. MicroRNA-21 induces resistance to 5-fluorouracil by down-regulating human DNA MutS homolog 2 (hMSH2). (2010). Proc of Natl Acad of Sci. USA. 107: 21098–103. PMID: 21078976 PMCID: PMC3000294 DOI: 10.1073/pnas.1015541107