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CLOVES Syndrome
Published in Dongyou Liu, Handbook of Tumor Syndromes, 2020
PIK3CA-related overgrowth spectrum (or PIK3CA-associated overgrowth) comprises a group of overgrowth disorders that are attributed to activating somatic mutations in the PIK3CA gene. These include CLOVES syndrome, fibroadipose hyperplasia or overgrowth (FAO), macrodactyly, megalencephaly-capillary malformation (MCAP) syndrome, hemihyperplasia multiple lipomatosis (HHML), macrodactyly, hemimegalencephaly, muscle hemihyperplasia, fibroadipose infiltrating lipomatosis, Klippel−Trenaunay syndrome (KTS), epidermal nevi, seborrheic keratoses, and benign lichenoid keratoses [5].
Inhibitors of phosphoinositide 3-kinase (PI3K) and phosphoinositide 3-kinase-related protein kinase family (PIKK)
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2023
Xueqin Huang, Li You, Eugenie Nepovimova, Miroslav Psotka, David Malinak, Marian Valko, Ladislav Sivak, Jan Korabecny, Zbynek Heger, Vojtech Adam, Qinghua Wu, Kamil Kuca
Miransertib is a novel oral AKT inhibitor that blocks membrane translocation of inactive AKT and dephosphorylates active AKT, thereby disrupting AKT activity269. Miransertib was initially used to treat human malignant tumours, but in recent years it has primarily been used to treat a variety of rare disorders, including PIK3CA-related overgrowth spectrum caused by somatic activating mutations in PIK3CA and Proteus syndrome caused by somatic activation in AKT1255,269. As a result, targeting the PI3K pathway offers promise for treating such diseases, and several clinical studies have been performed with miransertib to treat related diseases. Furthermore, miransertib has a curative impact on visceral and cutaneous leishmaniasis270.
End of induction patient reported outcomes predict clinical remission and endoscopic improvement with vedolizumab and adalimumab in ulcerative colitis
Published in Scandinavian Journal of Gastroenterology, 2023
Emily Chu Lee Wong, Badar Hasan, Parambir S. Dulai, John K. Marshall, Walter Reinisch, Neeraj Narula
While rapid improvement in symptoms is important for patients, whether PRO improvement earlier than post-induction is similarly predictive of long-term outcomes remains unclear. In our analysis, we observed that patients with severely elevated PROs at week 2 were less likely to achieve EI at one year after adjustment for known confounders. This has important implications for patients and clinicians as evaluation of PROs as early as two weeks after starting therapy can be used to guide treatment decision-making. However, patients may have a delayed response to therapy and have symptoms that may persist for reasons unrelated to UC, such as irritable bowel syndrome, bile acid malabsorption, viral infections, or hemorrhoids. Therefore, treatment decisions should be made given the totality of evidence, with consideration given to early changes in PROs. Strengths of this study include using data used from a randomized, double-blind, multicenter, clinical trial with centrally read endoscopy. However, we also acknowledge some limitations in our study. There is the potential for treatment bias since all patients enrolled in the study received an active comparator (either received vedolizumab or adalimumab) that could influence PROs. Secondly, the patient population in our study was relatively young (mean age 40.7 years) with short disease duration, with their PROs likely to be reliable, but the application of our findings in the elderly population or those with longer disease duration is uncertain. There also may be some selection bias in that patients enrolled in the VARSITY study had moderate to severe disease, so it is possible these findings may not apply to those with milder or more severe disease. Dose intensification of vedolizumab and adalimumab was not permitted in the VARSITY trial, which may limit the generalizability of our findings. However, as non-response at the end of induction is a negative predictor for one-year outcomes, our findings support the role of early drug optimization as a strategy to improve outcomes for patients. Lastly, multiple comparisons were performed to identify potential trends or associations; however, we adjusted the p-value threshold to account for multiple comparisons. Small sample sizes in subgroups, particularly among patients with severe rectal bleeding, is a notable limitation of our analysis, and limits further extrapolation.
Phosphatidylinositol 3-kinase (PI3K) inhibitors: a recent update on inhibitor design and clinical trials (2016–2020)
Published in Expert Opinion on Therapeutic Patents, 2021
Dima A. Sabbah, Rima Hajjo, Sanaa K. Bardaweel, Haizhen A. Zhong
Dactolisib (or BEZ235) (47) is a dual PI3K/mTOR inhibitor and is under clinical investigation for use in hematological malignancies (NCT01756118) [124]. A recent patent shows that improved efficacy was observed in the combination therapy of dactolisib (47) with anti-CD19 antibody drug conjugate (ADC) [125]. A recent patent reports the combination therapy of serabelisib (10) with metformin, or GDC-0077 with an ER antagonist fulvestrant, or GDC-0077 with non-steroidal aromatase inhibitor letrozole has been registered in clinical trials with enrolling patients with locally advanced or metastatic PIK3CA-mutant HR+/HER2- breast cancer [126]. A combination of GDC-0077 with fulvestrant, or with CDK4 inhibitor palbociclib was reported in a recent patent [127]. Omipalisib (GSK2126458), dactolisib (or BEZ235) (47), and alpelisib (BYL719, 9) are reported to treat squamous cell carcinoma (SCC) in various cell lines with different PIK3CA mutants, including the commonly observed H1047R and E542K mutants [128]. In a phase III clinical trial, taselisib (11), a potent, selective PI3K inhibitor, combined with standard hormone therapy fulvestrant (Faslodex) arrested the growth of advanced breast cancer by 2 months longer than hormone therapy alone (NCT02340221) [76]. Taselisib (11) was shown in a patent to inhibit HCC1954 breast cancer cells that contains PIK3CA H1047R mutant at 0.18 µM concentration [129]. In GY008 study, copanlisib (3) mono-treatment demonstrated limited activity in patients with persistent or recurrent endometrial cancer harboring hotspot PIK3CA mutations [130]. In addition, in an open-label phase 1/2 trial, combination of copanlisib and gemcitabine appears to be a safe and effective treatment strategy in relapsed/refractory peripheral T-cell lymphomas (PTCLs) [131]. A patent shows that the combination of copanlisib (3) with triazolone derivatives led to a significantly reduced tumor volume in diffuse large B-cell lymphoma (TMD8) xenograft model [132]. Isoindolone II (48) was shown to inhibit PI3Kδ and PI3Kγ with IC50 values of 0.7 and 0.9 nM, respectively [133]. ARQ 092 blocks AKP phosphorylation and activation of neutrophils and platelets isolated from sickle cell disease mice ex vivo [134]. A robust efficacy was observed in alpelisib (9)-treated patients with PIK3CA-related overgrowth spectrum (PROS-CLOVES syndrome) [135]. A combination of alpelisib and B-RAF inhibitor dabrafenib was used to treat various types of lymphoma and leukemia [136]. Addition of PDK1 inhibitors such as GSK2334470 and BX-795 to alpelisib treatment was reported to sensitize alpelisib-resistant cells [137]. The combination of buparlisib (NVP-BKM 120) (1) with the WNT pathway inhibitor (WNT974) significantly reduced tumor size [138]. A combination treatment of pictilisib (GDC-0941) with ERK inhibitor shows synergistic effect [139].