Any Role of PIK3CA and PTEN Biomarkers in the Prognosis in Oral Squamous Cell Carcinoma?

Oral squamous cell carcinoma (OSCC) accounts for 95% of the lesions in the oral cavity. Despite development in OSCC management, the outcome is still unsatisfactory. Identification of new therapies in OSCC is urgently needed. One objective of such treatment may be a signaling pathway of phosphatidylinositol 3-kinase. The study group included 92 patients treated for OSCC at the University Clinical Centre in Gdańsk, Poland. Study was performed on formalin-fixed paraffin-embedded samples from primary OSCC. Phosphatidylinositol-4,5-bisphosphate 3-kinase (PIK3CA) and phosphatase and tensin homolog encoded on chromosome 10 (PTEN) protein expression was assessed by immunohistochemistry (IHC). PIK3CA gene copy number was analyzed using chromogenic and silver in situ hybridization where molecular probes are marked by chromogens and silver ions. PIK3CA IHC H-score ≥ 70 was found in 51.65% patients, and loss of PTEN protein was noticed in 31.46% cases. PIK3CA amplification was detected in 5 tumors. In the case of PTEN protein expression, there was an inverse correlation with the T stage of the primary tumor (r = −0.243) and positive correlation with a 5-year survival (r = 0.235). The number of copies of the PIK3CA gene was associated with the tumor grading (r = 0.208). The present study shows that loss of PTEN protein and the grading (p = 0.040), distant metastases (p = 0.033), smoking (p = 0.016), and alcohol abuse (p = 0.042) were prognostic factors for the survival of patients with OSCC. In contrast, the presence of amplification and OSCC on the floor of the mouth resulted in a nearly six-fold increase in the risk of shortening survival (p = 0.037). Our finding suggests a potential prognostic significance of PTEN loss and PIK3CA amplification in OSCC. Future studies are needed to confirm our results.

Detection of PIK3R1 (L449S) Mutation in a Patient with Ovarian Cancer: A Case Report

Ovarian cancer (OC) is one of the most dangerous gynecological diseases and greatly increases the death risk worldwide. The heterogeneity of the ovarian tumors among patients and the lack of sufficient therapies for these tumors make the selection of the appropriate treatment a hard challenge. Understanding the mechanisms leading to OC becomes an urgent need in order to find out better therapeutic strategies. In this study, we have identified a point mutation (L449S) in the regulatory subunit of PI3K in an OC Lebanese patient. This genomic alteration had not been previously reported in OC and could plausibly enhance the PIK3CA amplification effect in strengthening AKT/mTOR pathway activity and leading to tumorigenesis.

Co-amplification of MET and PIK3CA in NSCLC and data on a PDX mouse model.

11591 Background: Amplification of the mesenchymal-epithelial transition ( MET) proto-oncogene or phosphatidylinositol3-kinase ( PI3K) is common in non-small-cell lung cancer (NSCLC) and represents a potential therapeutic target. NSCLC with coexisting driver mutations or amplifications is a cause of great concern. Methods: From 2013 until now, fluorescence in situ hybridization was used to screen for MET amplified NSCLC patients.The amplification of the MET was defined as centromere 7 ratio ≥ 2.0 and the criterion of Cappuzzi. The amplification of the PIK3CA was copy numbers ≥ 4.0. We established the patient-derived exnograft (PDX) mouse model from a dual MET/PIK3CA-amplified patient. Preclinical efficacy of single versus dual inhibition was evaluated in vivo. Six groups were allocated to receive the treatment of vehicle control, bozitinib,crizotinib, taselisib (PI3K inhibitor), bozitinib+taselisib, or crizotinib+taselisib, respectively. Results: Totally, 568 (568/2321, 24.47%) patients harbored positive MET amplification and 6 (6/568,1%) were comfirmed with dual MET/PI3K amplification. The two stageⅣ patients received MET inhibitor treatment.One trial (NCT02896231) patient was treated with bozitinib and achieved confirmed PR, but with 3 months PFS and 5 months OS. The best response was PR and PFS was 5.6 months for the other one receiving the study drug capmatinib (NCT02276027). In the PDX mouse model experiment, we found three single-anget inhibitors monotherapy to be active but only transiently effective in controlling the growth of PDX. The PDX models showed more sensitivity to taselisib among the three single-anget groups. In contrast, the combination of the two inhibitors caused a stronger and long-lasting growth inhibition in PDX models. The addition of taselisib to bozitinib or crizotinib monotherapy provided obvious enhanced activity. Regretfully, two mice died because of the toxicities in the crizotinib+taselisib group. Conclusions: Patients with dual MET/PIK3CA amplification represent a rare molecular subtype of NSCLC and have a relatively short duration of response to MET inhibitors.The combination of MET/PI3K inhibitors is synergistic preclinically.