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Small-Molecule Targeted Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Taselisib (GDC-0032) was developed by Genentech/Roche and licensed by Chugai Pharmaceutical targets. It targets PIK3CA and reached Phase III clinical trials for the treatment of metastatic breast and non-small-cell lung cancer. However, in 2018 Roche decided to discontinue the agent after clinical data showed only a short 2-month progression-free survival advantage for the drug combined with fulvestrant in metastatic breast cancer, along with significant systemic toxicities.
How much pharmacological therapy can be incorporated in venous malformations management?
Published in Byung-Boong Lee, Peter Gloviczki, Francine Blei, Jovan N. Markovic, Vascular Malformations, 2019
At this time, there are reports citing treatment with sirolimus/everolimus, miransertib (ARQ 092), alpelisib BYL719, taselisib, octreotide, brimonidine 0.33% gel, sildenafil, topical timolol maleate, propranolol, tetracycline derivatives, doxycycline, statins, bevacizumab/ranibizumab, thalidomide/pomalidomide, pazopanib, in patients with vascular malformations. As previously noted, the rationale for many of these therapies derives from the identification of somatic or genomic mutations in these disorders, with subsequent elucidation of the biological pathways. Targeted therapies are now a reality (Figure 43.1).
Heterogeneity of triple-negative breast cancer: understanding the Daedalian labyrinth and how it could reveal new drug targets
Published in Expert Opinion on Therapeutic Targets, 2022
Alberto Zambelli, Riccardo Sgarra, Rita De Sanctis, Elisa Agostinetto, Armando Santoro, Guidalberto Manfioletti
Interestingly, the expression of retinoblastoma protein (Rb), the product of the RB tumor suppressor gene, tends to be associated with AR expression in TNBC [99]. This observation suggests a luminal-like biology despite the TNBC subtype, and support the hypothesis of increased efficacy by combining anti-androgens with CDK4-6 inhibitors for these tumors [99]. A phase II study evaluating the combination of bicalutamide with palbociclib for AR-positive TNBC showed that this dual treatment was safe and active, with 33% of patients (11/33) progression-free at 6 months [100]. A phase II study (NCT03090165) is evaluating the combination of bicalutamide and ribociclib in AR-positive advanced TNBC. Moreover, the combination of the anti-androgen blockade with the inhibition of PI3K pathway is another promising strategy. The addition of taselisib to enzalutamide has been tested in a phase I/II study and showed higher benefit in patients with LAR TNBC compared to those with non-LAR disease (CBR: 75% and 12.5%, respectively, p = 0.06; PFS 4.6 vs. 2.0 months, respectively, p = 0.082) [101]. A phase I study testing another PI3K-inhibitor, alpelisib, in combination with enzalutamide in patients with AR and PTEN-positive metastatic BC is ongoing (NCT03207529).
Alpelisib for the treatment of PIK3CA-mutated, hormone receptor-positive, HER2-negative metastatic breast cancer
Published in Expert Opinion on Pharmacotherapy, 2021
Fanny Leenhardt, Marie Alexandre, William Jacot
Finally, alpelisib’s toxicity profile is a significant pitfall. Targeting the alpha isoform of PI3K certainly allows avoidance of the psychiatric effects that are reported with buparlisib and some of the colitis that is reported with taselisib [35,36]. However, hyperglycemia seems to occur even more frequently with alpelisib than with its predecessors. Very strict selection of the patient population appears mandatory. Indeed, in SOLAR-1 [28], with a population selected for a clinical research study, 60% of the population was classified as diabetic or prediabetic based on their fasting blood glucose and HbA1c levels. In view of the incidence and severity of this side effect, validated strategies evaluating prophylactic treatment or early management are necessary. Otherwise, it may seem prudent, in the absence of additional data, not to prescribe this compound in this high-risk population in the absence of a demonstrated superiority over its comparators, everolimus and CDKi.
PI3K inhibition to overcome endocrine resistance in breast cancer
Published in Expert Opinion on Investigational Drugs, 2018
Niamh M Keegan, Jack P Gleeson, Bryan T Hennessy, Patrick G Morris
Taselisib has also been studied in combination with letrozole with satisfactory safety and is now being tested in the phase II setting in early breast cancer preoperatively in the double blind, multicentre, large phase II placebo controlled, LORELEI study (NCT02273973). Patients are randomized to receive letrozole with taselisib or placebo for 16 weeks before surgery with co-primary endpoints of pathological complete response and ORR by MRI [71,72]. This study demonstrated an increased ORR by MRI from 38% to 56.2% for the combination in the PIK3CA mutated subset (N = 152; OR = 2.03, [1.06–3.88], p = 0.033) and in all randomized patients f pts (from 39.3% to 50%, OR 1.55, 95%CI 1.00–2.38, p = 0.049). No significant difference was observed for pCR rate overall or in the PIK3CA mutated subset [72].