Doxorubicin as a fluorescent reporter identifies novel MRP1 (ABCC1) inhibitors missed by calcein-based high content screening of anticancer agents

2 views | Aug 13 2019

Sampson A et al. indicated mifepristone and doramapimod as pan inhibitors of these three drug transporters while celecoxib exhibited selective MRP1 inhibition. Together, our findings signify the importance of MRP1 in drug discovery and demonstrate the effectiveness and value of doxorubicin-based high content screening approach. Anti-cancer agents that exhibit MRP1 inhibition may be used to reverse multidrug resistance or to improve the efficacy and reduce the toxicity of various cancer chemotherapies. On the other hand, anti-cancer drugs that did not interact with MRP1 carry a low risk for developing MRP1-mediated resistance. [Read the Full Post]

BYL719, a new α-specific PI3K inhibitor: single administration and in combination with conventional chemotherapy for the treatment of osteosarcoma

7 views | Jul 31 2019

Gobin B et al. indicated the present work shows that BYL719 is a promising drug in either a single or multidrug approach to curing bone sarcoma. [Read the Full Post]

A Phase Ib Study of Alpelisib (BYL719), a PI3Kα-Specific Inhibitor, with Letrozole in ER+/HER2- Metastatic Breast Cancer

0 views | Jul 31 2019

Mayer IA et al. showed that alpelisib's maximum-tolerated dose (MTD) in combination with letrozole was 300 mg/d. Common drug-related adverse events included hyperglycemia, nausea, fatigue, diarrhea, and rash with dose-limiting toxicity occurring at 350 mg/d of alpelisib. The clinical benefit rate (lack of progression ≥6 months) was 35% (44% in patients with PIK3CA-mutated and 20% in PIK3CA wild-type tumors; 95% CI, 17%-56%), including five objective responses. Of eight patients remaining on treatment ≥12 months, six had tumors with a PIK3CA mutation. Among evaluable tumors, those with FGFR1/2 amplification and KRAS and TP53 mutations did not derive clinical benefit. Overexpression of FGFR1 in ER+/PIK3CA mutant breast cancer cells attenuated the response to alpelisib in vitro CONCLUSIONS: The combination of letrozole and alpelisib was safe, with reversible toxicities. Clinical activity was observed independently of PIK3CA mutation status, although clinical benefit was seen in a higher proportion of patients with PIK3CA-mutated tumors. Phase II and III trials of alpelisib and endocrine therapy in patients with ER+ breast cancer are ongoing. [Read the Full Post]

Signaling pathways and inhibitors of cells from patients with kaposiform lymphangiomatosis

53 views | Jul 13 2019

Boscolo E et al. demonstrated that cells from KLA patient lesions are highly proliferative and the PI3K-AKT-mTOR and MAPK pathways are promising therapeutic targets. [Read the Full Post]

Low-intensity pulsed ultrasound promotes the proliferation of human bone mesenchymal stem cells by activating PI3K/AKt signaling pathways

69 views | May 18 2019

Xie S et al. suggested that LIPUS exposure may be involved in the proliferation of hBMSCs via activation of the PI3K/AKt signaling pathway and high expression of cyclin D1, and the intensity of 50 or 60 mW/cm2 and exposure time of 5 minutes were determined to be the optimal parameters for LIPUS exposure. [Read the Full Post]

Update Breast Cancer 2019 Part 2 - Implementation of Novel Diagnostics and Therapeutics in Advanced Breast Cancer Patients in Clinical Practice

47 views | May 10 2019

This review summarises the latest studies and publications and evaluates them in regard to the relevance for clinical practice. [Read the Full Post]

The HSP90 inhibitor, NVP-AUY922, attenuates intrinsic PI3K inhibitor resistance in KRAS-mutant non-small cell lung cancer

76 views | Apr 19 2019

Park KS et al. indicated that dual inhibition of the HSP90 and PI3K signaling pathways with sub-therapeutic doses of these combined anticancer drugs may represent a potent treatment strategy for KRAS-mutant NSCLC with intrinsic resistance to PI3K inhibition. [Read the Full Post]

The dual PI3K/mTOR inhibitor GSK2126458 is effective for treating solid renal tumours in Tsc2+/- mice through suppression of cell proliferation and induction of apoptosis

0 views | Apr 19 2019

Narov K et al. found that both GSK2126458 and rapamycin caused significant reduction in number and size of solid renal tumours. GSK2126458 also significantly reduced the number and size of all lesions (cystic, papillary and solid) although to a lesser extent compared to rapamycin. GSK2126458 inhibited both PI3K and mTOR while rapamycin exerted stronger inhibitory effect on mTORC1 in renal tumours. Furthermore, GSK2126458 and rapamycin suppressed proliferation of tumour cells. Importantly, GSK2126458 increased apoptosis of solid tumours but rapamycin did not. Further investigations are therefore needed to test whether rapamycin in combination with GSK2126458 could promote apoptosis and thus improve therapy of TSC-associated renal tumours. [Read the Full Post]

Copanlisib: An Intravenous Phosphatidylinositol 3-Kinase (PI3K) Inhibitor for the Treatment of Relapsed Follicular Lymphoma

68 views | Apr 18 2019

Eltantawy A et al. indicated Copanlisib provides an alternative option for patients with relapsed FL. It is safe and effective and has an acceptable toxicity profile. [Read the Full Post]

Chemoproteomic Selectivity Profiling of PIKK and PI3K Kinase Inhibitors

77 views | Apr 12 2019

Reinecke M et al. showed that NVP-BEZ235 is not a PI3K inhibitor. Surprisingly, the designated ATM inhibitor CP466722 was found to bind strongly to ALK2, identifying a new chemotype for drug discovery to treat fibrodysplasia ossificans progressiva. [Read the Full Post]