Role of BRAF in Hepatocellular Carcinoma: A Rationale for Future Targeted Cancer Therapies

The few therapeutic strategies for advance hepatocellular carcinoma (HCC) on poor knowledge of its biology. For several years, sorafenib, a tyrosine kinase inhibitors (TKI) inhibitor, has been the approved treatment option, to date, for advanced HCC patients. Its activity is the inhibition of the retrovirus-associated DNA sequences protein (RAS)/Rapidly Accelerated Fibrosarcoma protein (RAF)/mitogen-activated and extracellular-signal regulated kinase (MEK)/extracellular-signal regulated kinases (ERK) signaling pathway. However, the efficacy of sorafenib is limited by the development of drug resistance, and the major neuronal isoform of RAF, BRAF and MEK pathways play a critical and central role in HCC escape from TKIs activity. Advanced HCC patients with a BRAF mutation display a multifocal and/or more aggressive behavior with resistance to TKI. Moreover, also long non-coding RNA (lnc-RNA) have been studied in epigenetic studies for BRAF aggressiveness in HCC. So far, lnc-RNA of BRAF could be another mechanism of cancer proliferation and TKI escape in HCC and the inhibition could become a possible strategy treatment for HCC. Moreover, recent preclinical studies and clinical trials evidence that combined treatments, involving alternative pathways, have an important role of therapy for HCC and they could bypass resistance to the following TKIs: MEK, ERKs/ribosomal protein S6 kinase 2 (RSK2), and phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR). These initial data must be confirmed in clinical studies, which are currently ongoing. Translational research discoveries could create new strategies of targeted therapy combinations, including BRAF pathway, and they could eventually bring light in new treatment of HCC

Co-targeting of Bcl-2 and mTOR pathway triggers synergistic apoptosis in BH3 mimetics resistant acute lymphoblastic leukemia

Several chemo-resistance mechanisms including the Bcl-2 protein family overexpression and constitutive activation of the PI3K/Akt/mTOR signaling have been documented in acute lymphoblastic leukemia (ALL), encouraging targeted approaches to circumvent this clinical problem. Here we analyzed the activity of the BH3 mimetic ABT-737 in ALL, exploring the synergistic effects with the mTOR inhibitor CCI-779 on ABT-737 resistant cells. We showed that a low Mcl-1/Bcl-2 plus Bcl-xL protein ratio determined ABT-737 responsiveness. ABT-737 exposure further decreased Mcl-1, inducing apoptosis on sensitive models and primary samples, while not affecting resistant cells. Co-inhibition of Bcl-2 and the mTOR pathway resulted cytotoxic on ABT-737 resistant models, by downregulating mTORC1 activity and Mcl-1 in a proteasome-independent manner. Although Mcl-1 seemed to be critical, ectopic modulation did not correlate with apoptosis changes. Importantly, dual targeting proved effective on ABT-737 resistant samples, showing additive/synergistic effects. Together, our results show the efficacy of BH3 mimetics as single agent in the majority of the ALL samples and demonstrate that resistance to ABT-737 mostly correlated with Mcl-1 overexpression. Co-targeting of the Bcl-2 protein family and mTOR pathway enhanced drug-induced cytotoxicity by suppressing Mcl-1, providing a novel therapeutic approach to overcome BH3 mimetics resistance in ALL

Epilepsy With Auditory Features: From Etiology to Treatment

Epilepsy with auditory features (EAF) is a focal epilepsy belonging to the focal epileptic syndromes with onset at variable age according to the new ILAE Classification. It is characterized by seizures with auditory aura or receptive aphasia suggesting a lateral temporal lobe involvement of the epileptic discharge. Etiological factors underlying EAF are largely unknown. In the familial cases with an autosomal dominant pattern of inheritance several genes have been involved, among which the first discovered, LGI1, was thought to be predominant. However, increasing evidence now points to a multifactorial etiology, as familial and sporadic EAF share a virtually identical electro-clinical characterization and only a few have a documented genetic etiology. Patients with EAF usually have an unremarkable neurological examination and a good response to antiseizure medications. However, it must be underscored that total remission might be lower than expected and that treatment withdrawal might lead to relapses. Thus, a proper understanding of this condition is in order for better patient treatment and counseling. Further studies are still required to further characterize the many facets of EAF

Immunotherapeutic approaches for hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is a cancer with a high mortality rate due to the fact that the diagnosis usually occurs at anadvanced stage. Even in case of curative surgical treatment, recurrence is common. Sorafenib and regorafenib are the only therapeutic agents that have been demonstrated to be effective in advanced HCC, thus novel curative approaches are urgently needed. Recent studies focus on the role of immune system in HCC. In fact, the unique immune response in the liver favors tolerance, which can represent a real challenge for conventional immunotherapy in these patients. Spontaneous immune responses against tumor antigens have been detected, and new immune therapies are under investigation: dendritic cell vaccination, immune-modulator strategy, and immune checkpoint inhibition. In recent years different clinical trials examining the use of immunotherapy to treat HCC have been conducted with initial promising results. This review article will summarize the literature data concerning the potential immunotherapeutic approaches in HCC patient

Epilepsy and inborn errors of metabolism in adults: The diagnostic odyssey of a young woman with medium-chain acyl-coenzyme A dehydrogenase deficiency

We describe a case of epileptic encephalopathy in a young woman with undiagnosed medium-chain acyl-coenzyme A dehydrogenase deficiency (MCADD), who presented with an early-onset focal motor status epilepticus (SE) then followed by permanent left hemiplegia and drug-resistant epilepsy with neurodevelopmental delay. Throughout her clinical history, recurrent episodes of lethargy, feeding difficulties, and clustering seizures occurred, progressing into a super refractory SE and death at the age of 25 years. Although epilepsy is not a distinctive feature of MCADD, we advise considering this metabolic disease as a possible etiology of epileptic encephalopathy and hemiconvulsion-hemiplegia-epilepsy syndrome of unknown origin, on the chance to provide a timely and targeted treatment preventing development delay and evolution to SE. Adult patients with epilepsy of unknown etiology not screened at birth for inborn errors of metabolism, such as MCADD, should be promptly investigated for these treatable conditions

Co-targeting of Bcl-2 and mTOR pathway triggers synergistic apoptosis in BH3 mimetics resistant acute lymphoblastic leukemia

: Several chemo-resistance mechanisms including the Bcl-2 protein family overexpression and constitutive activation of the PI3K/Akt/mTOR signaling have been documented in acute lymphoblastic leukemia (ALL), encouraging targeted approaches to circumvent this clinical problem. Here we analyzed the activity of the BH3 mimetic ABT-737 in ALL, exploring the synergistic effects with the mTOR inhibitor CCI-779 on ABT-737 resistant cells. We showed that a low Mcl-1/Bcl-2 plus Bcl-xL protein ratio determined ABT-737 responsiveness. ABT-737 exposure further decreased Mcl-1, inducing apoptosis on sensitive models and primary samples, while not affecting resistant cells. Co-inhibition of Bcl-2 and the mTOR pathway resulted cytotoxic on ABT-737 resistant models, by downregulating mTORC1 activity and Mcl-1 in a proteasome-independent manner. Although Mcl-1 seemed to be critical, ectopic modulation did not correlate with apoptosis changes. Importantly, dual targeting proved effective on ABT-737 resistant samples, showing additive/synergistic effects. Together, our results show the efficacy of BH3 mimetics as single agent in the majority of the ALL samples and demonstrate that resistance to ABT-737 mostly correlated with Mcl-1 overexpression. Co-targeting of the Bcl-2 protein family and mTOR pathway enhanced drug-induced cytotoxicity by suppressing Mcl-1, providing a novel therapeutic approach to overcome BH3 mimetics resistance in ALL

Current management of primary mitochondrial disorders in EU countries: the European Reference Networks survey

Background and purpose: Primary mitochondrial diseases (PMDs) are rare diseases for which diagnosis is challenging, and management and training programs are not well defined in Europe. To capture and assess care needs, five different European Reference Networks have conducted an exploratory survey. Methods: The survey covering multiple topics relating to PMDs was sent to all ERNs healthcare providers (HCPs) in Europe. Results: We have collected answers from 220 members based in 24/27 European member states and seven non-European member states. Even though most of the responders are aware of neurogenetic diseases, difficulties arise in the ability to deliver comprehensive genetic testing. While single gene analysis is widely available in Europe, whole exome and genome sequencing are not easily accessible, with considerable variation between countries and average waiting time for results frequently above 6 months. Only 12.7% of responders were happy with the ICD-10 codes for classifying patients with PMDs discharged from the hospital, and more than 70% of them consider that PMDs deserve specific ICD codes to improve clinical management, including tailored healthcare, and for reimbursement reasons. Finally, 90% of responders declared that there is a need for further education and training in these diseases. Conclusions: This survey provides information on the current difficulties in the care of PMDs in Europe. We believe that the results of this survey are important to help rare disease stakeholders in European countries identify key care and research priorities

Epilepsy with auditory features: A heterogeneous clinico-molecular disease

Objective: To identify novel genes implicated in epilepsy with auditory features (EAF) in phenotypically heterogeneous families with unknown molecular basis. Methods: We identified 15 probands with EAF in whom an LGI1 mutation had been excluded. We performed electroclinical phenotyping on all probands and available affected relatives. We used whole-exome sequencing (WES) in 20 individuals with EAF (including all the probands and 5 relatives) to identify single nucleotide variants, small insertions/deletions, and copy number variants. Results: WES revealed likely pathogenic variants in genes that had not been previously associated with EAF: a CNTNAP2 intragenic deletion, 2 truncating mutations of DEPDC5, and a missense SCN1A change. Conclusions: EAF is a clinically and molecularly heterogeneous disease. The association of EAF with CNTNAP2, DEPDC5, and SCN1A mutations widens the phenotypic spectrum related to these genes. CNTNAP2 encodes CASPR2, a member of the voltage-gated potassium channel complex in which LGI1 plays a role. The finding of a CNTNAP2 deletion emphasizes the importance of this complex in EAF and shows biological convergence

Co-targeting of Bcl-2 and mTOR pathway triggers synergistic apoptosis in BH3 mimetics resistant acute lymphoblastic leukemia

Several chemo-resistance mechanisms including the Bcl-2 protein family overexpression and constitutive activation of the PI3K/Akt/mTOR signaling have been documented in acute lymphoblastic leukemia (ALL), encouraging targeted approaches to circumvent this clinical problem. Here we analyzed the activity of the BH3 mimetic ABT-737 in ALL, exploring the synergistic effects with the mTOR inhibitor CCI-779 on ABT-737 resistant cells. We showed that a low Mcl-1/Bcl-2 plus Bcl-xL protein ratio determined ABT-737 responsiveness. ABT-737 exposure further decreased Mcl-1, inducing apoptosis on sensitive models and primary samples, while not affecting resistant cells. Co-inhibition of Bcl-2 and the mTOR pathway resulted cytotoxic on ABT-737 resistant models, by downregulating mTORC1 activity and Mcl-1 in a proteasome-independent manner. Although Mcl-1 seemed to be critical, ectopic modulation did not correlate with apoptosis changes. Importantly, dual targeting proved effective on ABT-737 resistant samples, showing additive/synergistic effects. Together, our results show the efficacy of BH3 mimetics as single agent in the majority of the ALL samples and demonstrate that resistance to ABT-737 mostly correlated with Mcl-1 overexpression. Co-targeting of the Bcl-2 protein family and mTOR pathway enhanced drug-induced cytotoxicity by suppressing Mcl-1, providing a novel therapeutic approach to overcome BH3 mimetics resistance in ALL