Background/Aim: Medulloblastoma (MB) accounts for ~20% of pediatric malignant central nervous system tumors. Treatment strategies, including surgery, radiation therapy and/or chemotherapy, are effective, but recurrence and metastasis frequently occur. Therefore, novel therapies are required. Herein, the effects of fibroblast growth factor receptor (FGFR) and phosphoinositide 3-kinase (PI3K) inhibitors on MB cells lines were evaluated. Materials and Methods: MB cell lines (UW228-3, DAOY, Med8a, D425, D283) were tested for sensitivity to FGFR (AZD4547) and PI3K (BEZ235 and BYL719) inhibitors by viability, cytotoxicity, apoptosis, and proliferation assays. Results: Single treatments with FGFR and PI3K inhibitors decreased viability and proliferation in a dose-dependent pattern in most cell lines. Combinination of the two type of drugs, increased sensitivity, especially of the most resistant cell line UW228-3. Conclusion: Combination treatments with FGFR and PI3K inhibitors were superior to single treatments with FGFR and PI3K inhibitors, especially with BEZ235, for MB cell lines.

Objectives: Human papillomavirus positive (HPV⁺) tonsillar and base of tongue squamous cell carcinoma (TSCC/BOTSCC), the major subsites of oropharyngeal squamous cell carcinoma (OPSCC) have favorable outcome, but upon relapse, outcome is poor and new therapies needed. Since, phosphatidyl-inositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA) and fibroblast-growth-factor-receptor-3 (FGFR3) mutations often occur in such tumors, here, we tested targeted therapy directed to such genes in TSCC/BOTSCC cell lines. We also combined the two types of inhibitors with each other, and cisplatin or docetaxel that are used clinically.Methods: The HPV⁺ CU-OP-2, -3, -20, UPCI-SCC-154, and HPV^- CU-OP-17 and UT-SCC-60A cell lines were first tested for common PIK3CA/FGFR3 mutations by competitive-allele-specific TaqMan-PCR. They were then treated with the food and drug administration (FDA) approved drugs, alpelisib (BYL719) and erdafitinib (JNJ-42756493) alone and in combination with cisplatin or docetaxel. Viability, proliferation, apoptosis and cytotoxicity responses were thereafter followed by WST-1 assays and the IncuCyte S3 Live^® Cell Analysis System.Results: HPV⁺ CU-OP-2 had a pS249C-FGFR3, and like CU-OP-20, a pE545K-PIK3CA mutation, while no other lines had such mutations. Irrespectively, dose dependent responses to all PI3K/FGFR inhibitors were obtained, and upon combining the inhibitors, positive effects were observed. Cisplatin and docetaxel also induced dose dependent responses, and upon combination with the inhibitors, both positive and neutral effects were found.Conclusions: The data suggest that FDA approved drugs alpelisib and erdafitinib efficiently inhibit TSCC/BOTSCC cell line growth, especially when combined irrespective of presence of corresponding mutations and should be further explored, for use upon recurrent disease.

Neuroblastoma (NB), comprising around 10% of all childhood neoplasms and 15% of pediatric cancer deaths is a heterogenous disease and can be divided into very low-, low-, intermediate- and high-risk NB. Treatment of very low/low-risk NB is usually based on observation, or surgery alone, whereas intermediate-risk NB is in addition to surgery treated with mild chemotherapy and roughly 80-95% of the patients are cured. In contrast, high-risk NB patients receive multimodal therapy with e.g. induction, consolidation, and maintenance therapy, which can include induction chemotherapy and surgery and in severe cases adding intensive chemotherapy and even autologous stem cell transplantation and radiotherapy. Unfortunately, however this treatment does not cure all patients and around 50% succumb to disease. For this purpose, new treatment options are urgently needed. In this review, we describe the complex molecular heterogeneity of NB, and potential new options for targeted therapy.

Medulloblastoma (MB) is the most frequent malignant brain tumor in children. Treatment of MB is based on histopathological and molecular stratification, and includes surgical intervention, often with craniospinal irradiation and adjuvant chemotherapy. Unfortunately, however, this treatment leads to a high morbidity rate, and it does not cure all patients either, with around 30% succumbing to their disease. With improved cancer genomics and better molecular characterization, MB has been classified into four major subgroups, wingless-activated, sonic hedgehog-activated, Group 3, and Group 4, with each group consisting of additional subtypes. Recently disclosed genetic drivers of MB may in the future help improve treatment, and in this way reduce therapy-related toxicity. In this review, we describe the heterogeneity of the MB subgroups, and potential new options for targeted therapy.

The incidence of Human-papillomavirus-positive (HPV⁺) tonsillar and base-of-tongue squamous cell carcinoma (TSCC and BOTSCC, respectively) is increasing epidemically, but they have better prognosis than equivalent HPV-negative (HPV⁻) cancers, with roughly 80% vs. 50% 3-year disease-free survival, respectively. The majority of HPV⁺ TSCC and BOTSCC patients therefore most likely do not require the intensified chemoradiotherapy given today to head and neck cancer patients and would with de-escalated therapy avoid several severe side effects. Moreover, for those with poor prognosis, survival has not improved, so better-tailored alternatives are urgently needed. In line with refined personalized medicine, recent studies have focused on identifying predictive markers and driver cancer genes useful for better stratifying patient treatment as well as for targeted therapy. This review presents some of these endeavors and briefly describes some recent experimental progress and some clinical trials with targeted therapy.

Neuroblastoma (NB) is a heterogenous disease with treatment varying from observation for low‑risk tumors, to extensive therapy with chemotherapy, surgery, radiotherapy, and autologous bone‑marrow‑transplantation and immunotherapy. However, a high frequency of primary‑chemo‑refractory disease and recurrences urgently require novel treatment strategies. The present study therefore investigated the anti‑NB efficacy of the recently FDA‑approved phosphoinositide 3‑kinase (PI3K) and fibroblast growth factor receptor (FGFR) inhibitors, alpelisib (BYL719) and erdafitinib (JNJ‑42756493), alone and in combination with or without cisplatin, vincristine, or doxorubicin on 5 NB cell lines. For this purpose, the NB cell lines, SK‑N‑AS, SK‑N‑BE(2)‑C, SK‑N‑DZ, SK‑N‑FI and SK‑N‑SH (where SK‑N‑DZ had a deletion of PIK3C2G and none had FGFR mutations according to the Cancer Program's Dependency Map, although some were chemoresistant), were tested for their sensitivity to FDA‑approved inhibitors alone or in combination, or together with cytostatic drugs by viability, cytotoxicity, apoptosis and proliferation assays. The results revealed that monotherapy with alpelisib or erdafitinib resulted in a dose‑dependent inhibition of cell viability and proliferation. Notably, the combined use of PI3K and FGFR inhibitors resulted in an enhanced efficacy, while their combined use with the canonical cytotoxic agents, cisplatin, vincristine and doxorubicin, resulted in variable synergistic, additive and antagonistic effects. Collectively, the present study provides pre‑clinical evidence that PI3K and FGFR inhibitors exhibit promising anti‑NB activity. The data presented herein also indicate that the incorporation of these inhibitors into chemotherapeutic regimens requires careful consideration and further research in order to obtain a beneficial efficacy. Nevertheless, the addition of PI3K and FGFR inhibitors to the treatment arsenal might reduce the occurrence of refractory and relapsing disease in NB without FGFR and PI3K mutations.