mTOR inhibition in breast cancer.
What is already known;
The mammalian target of rapamycin (mTOR) is a serine/threonine kinase and downstream member of the phosphatidylinositol-3-kinase (PI3K)/protein kinase B (AKT) and adenosine monophosphate-activated protein kinase (AMPK) pathways, with an essential role in cell growth, survival, and autophagy. mTOR is a component of two structurally similar complexes, mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2), which are however functionally distinct; mTORC1 promotes mRNA translation and protein synthesis by phosphorylation of ribosomal protein S6 kinase (S6K1) and eIF4E binding protein 1 (4E-BP1), and inhibits autophagy. mTORC2 organizes the cellular actin cytoskeleton and regulates AKT
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The luminal A subtype of breast cancer had the highest frequency of PIK3CA mutation (45%), and the basal subtype had the lowest (9%). Additional identified aberrations resulting in the dysregulation of the PI3K/mTOR pathway include Akt and PTEN mutations, or loss of PTEN protein [11,12].
The concept of mTOR inhibition in breast cancer was firstly supported by preclinical evidence demonstrating activation of the PI3K/mTOR pathway after long-term estrogen deprivation [13,14]; estrogen-deprived cells relied heavily on the PI3K signaling pathway, making this an important mechanism of acquired endocrine resistance. Combined use of anti-estrogens (tamoxifen/ letrosole) with rapamycin analogues demonstrated increased anti-tumour activity and reversal of endocrine resistance secondary to PI3K/mTOR activation in preclinical models [15-18].
In the metastatic setting, clinical trials using single agent mTOR inhibitors (everolimus/ temsirolimus) demonstrated modest activity with a response rate ranging between 9-12% [19-20]. In an effort to enrich for PIK3CA mutations, a clinical trial of temsirolimus alone in hormone receptor positive or HER-2 positive metastatic breast cancer patients, failed to demonstrate higher activity. PIK3CA mutations were not associated with a higher response rate, however it was the primary tumours that were analysed, and not the recurrent or metastatic sites, which may have obscured
Triple-negative breast cancers constitute about 15% of all cases, but despite their higher response to
Advances in MDS therapy will derive from molecular precision and identification of potential druggable targets for the disease. In 2005, The Cancer Genome Atlas (TCGA), and during 2008, The International Cancer Genome Consortium (ICGC) were designed as large-scale projects to improve understanding of cancer associated recurrent somatic mutations. In AML, robust prognostic relevant mutations were reported with mutational subgroups frequently observed in MDS suggesting similar ability to detect a significant impact on MDS outcome. Seven subgroups including activating signaling, DNA methylation, chromatin modifiers, spliceosome, myeloid transcription factors, tumor suppressor genes, and less commonly observed mutations including cohesin complex, BCOR, and BCORL1 (Fig.3). In this section, we will describe frequency, prognostic and functional implication of
Significance: understanding the mechanism of drug resistance in cancer leads to developing more potent drugs.
An effective breast cancer treatment in some women can be traced to the root of the disease. Some of the most aggressive form of breast cancers are caused by a transmembrane receptor protein known as Human Epidermal Growth Factor Receptor 2 (HER2) which is a member of the HER family of receptor tyrosine kinase. Approximately 20,000 HER2 receptor are normally expressed on surface of healthy breast cell however, in about 25% of breast cancer cells the HER2 protein is overexpressed resulting in tumour cells with as many as over 2 million receptors present on their surface. This cancer is known as HER2 positive (HER2+). The effect of HER2 overexpression is an increase in receptor mediated intracellular signalling causing the cell
The same treatment is not used for all types of breast cancers because these cancers differ in many ways and will respond differently to treatments. There is no known treatment that will help all four types of cancer.
A recent prospective study has demonstrated a substantial rate of discordance in hormone receptor status (40% discordance in ER/PgR status and 8% discordance in Her2 status) between primary and suspected metastatic lesions in women with breast cancer. This study has also linked changes in hormone receptor status with impact on management, and proved that 20% of patients had a significant change in their management plan (Simmons et al,
Mammalian target of rapamycin (mTOR) is a serine/threonine kinase in which this catalytic subunit forms into two distinct multiprotein complexes, mTORC1 and mTORC2 (Laplante et al., 2009 and Bar-Peled et al., 2014). The two multiprotein complexes share many similarities, but are still distinct from one another. Both complexes regulate anabolic processes such as cell survival, metabolism and proliferation. However, mTORC2 is known to play a key role in cytoskeleton organization to regulate cellular spatial growth (Laplante et al., 2009 and? ). While they share many functions, only mTORC1 coordinates these anabolic functions with upstream inputs such as: growth factors, energy status, and amino acid availability. mTORC1 is composed of five components: mTOR, the catalytic subunit; regulator-associated protein of mTOR (RAPTOR), scaffolding subunit; mammalian lethal with Sec13 protein 8 (mLST8); and two endogenous kinase inhibitors proline-rich AKT substrate 40kDa (PRAS40) and DEP-domain-containing mTOR-interacting protein (DEPTOR) (Laplante et al., 2009 and Bar-Peled et al., 2014 (5,6,7,8,9) and more). In order to effectively control cellular physiology, mTORC1 activation triggers a downstream signaling cascade to control such anabolic processes as protein synthesis and ribosomal biogenesis (). However, mTORC1 signaling cascade is regulated by small GTPase Rheb located at the lysosome surface and functions as a mTORC1 kinase activity stimulator under its active GTP-bound state (Bar-Peeled et al., 2014). Nevertheless, Rheb is also negatively regulated by tuberous sclerosis complex (TSC) 1 and 2 by exerting is
Mutations (for most cancers) must appear in both tumour suppressing genes and oncogenes for cancers to form. The tumour suppressing genes and oncogenes act in complementary fashion to one another; one pulls forward, and the other pushes back ensuring that the cell cycle occurs in a controlled manner (Sherr, 2004).
C-Akt, a serine-threonine kinase is one target of PI39K. C-Akt is the prototypical member of a mammalian Akt isoform family. The regulation to Akt may be phosphorylation or direct binding the Akt pleckstrin homology domain with PI39K lipid products. PI39K-independent Akt stimuli had been identified [3]. AMG 319 inhibited basal AKT phosphorylation and proliferation in lymphoid tumor cells [1].
Estrogens are vital for the regulation of sex hormones, and are known to proliferate certain forms of cancers. For this reason, estrogens are a recognized target for inhibition of hormone depended diseases like breast cancer, and aromatase inhibitors (AIs) like letrozole and anastrozole are of interest as they will lower the levels of estrogens. Both letrozole and anastrozole are currently indicated for the treatment of post-menopausal women with breast cancer.
Genomic research has shown that the presence of certain gene alterations/mutations can reliably predict the likelihood of clinical benefit using agents that inhibit the expression of defective genes responsible for carcinogenesis or DNA repair. Relevant to this case, is the demonstration of an altered ATM gene that appears to predict the sensitivity to PARP inhibitors, such as olaparib. Clinical responses have demonstrated in at least one clinical trial. 1 Olaparib has been granted “Breakthrough Therapy” designation by the US Food and Drug Administration (FDA) for treatment of metastatic castration-resistant prostate cancer harboring an ATM gene mutation. Based on similar data, olaparib has already received FDA-approval for use in treating metastatic ovarian cancer in patients having a BRCA 1/2 mutation. The benefit of “Breakthrough Therapy” designation is to expedite development of
Although there are precautions taken to achieve the best match for organs, the human immune system is not so easily fooled into accepting a foreign organ. And that’s where drugs like rapamycin comes in. Antirejection medication are immunosuppressants which suppress the patient’s immune system so that it cannot attack the transported organ. Rapamycin is a drug that is prescribed to kidney transplant patients so their immune systems are weaken enough to not identify the newly transported kidney as foreign and reject it.
Design: This was a Phase 1 trial to determine the MTD of ceritinib in adult patients with tumors harboring a genetic alteration in ALK. Secondary objectives were to characterize the safety and side-effect profile, pharmacokinetic profile, and antitumor activity of ceritinib.
The inhibitory effect of rapamycin on Kv channel activity suggests that Kv1.3 and/or Kv1.5 channels are regulated by mTOR. To test this hypothesis directly, cRNA encoding Kv1.3 or Kv1.5 was injected into Xenopus oocytes without or with additional injection of cRNA encoding mTOR. In Xenopus oocytes expressing Kv1.3, but not in waterinjected
Past studies have shown that Podxl overexpression identifies a highly aggressive subset of breast carcinomas. Moreover, our previous results show an important role of Podxl on in vivo primary tumor growth and metastasis of MDA-MB-231 cells. However, the mechanism of action by which Podxl plays a role in tumor progression it still unclear. I hypothesize that the structure and biochemical and signalling properties of podocalyxin promote breast cancer tumor progression and, therefore, podocalyxin may be a novel target for future therapeutics.