Glioblastoma multiforme (GBM) is known as the most aggressive and prevalent brain tumor with a high mortality rate. It is reported in people who are as young as 10 years old to as old as over 70 years old, exhibiting inter and intra tumor heterogeneity. There are several genomic and proteomic investigations that have been performed to find the unexplored potential targets of the drug against GBM. Therefore, certain effective targets have been taken to further validate the studies embarking on the robustness in the field of medicinal chemistry followed by testing in clinical trials. Also, The Cancer Genome Atlas (TCGA) project has identified certain overexpressed targets involved in the pathogenesis of GBM in three major pathways, i.e., tumor protein 53 (p53), retinoblastoma (RB), and receptor tyrosine kinase (RTK)/rat sarcoma virus (Ras)/phosphoinositide 3-kinase (PI3K) pathways. This review focuses on the compilation of recent developments in the fight against GBM thus, directing future research into the elucidation of pathogenesis and potential cure for GBM. Also, it highlights the potential biomarkers that have undergone extensive research and have promising prognostic and predictive values. Additionally, this manuscript analyses the advent of gene therapy and immunotherapy, unlocking the way to consider treatment approaches other than, or in addition to, conventional chemo-radiation therapies. This review study encompasses all the relevant research studies associated with the pathophysiology, occurrence, diagnostic tools, and therapeutic intervention for GBM. It highlights the evolution of various therapeutic perspectives against GBM from the most conventional form of radiotherapy to the recent advancement of gene/cell/immune therapy. Further, the review focuses on various targeted therapies for GBM including chemotherapy sensitization, radiotherapy, nanoparticles based, immunotherapy, cell therapy, and gene therapy which would offer a comprehensive account for exploring several facets related to GBM prognostics.

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Mitochondria are present in all mammalian cells except matured red blood cells. Mitochondria consist of several metabolic pathways for glucose, fatty acids, amino acids, and bioenergetic pathways for ATP synthesis, membrane potential, and reactive oxygen production. In the liver, hepatic mitochondria play a key role in hepatic steatosis because mitochondrial metabolism produces acetyl-CoA which is the building block for synthesis of lipids and cholesterol. Mitochondria inner membrane is impermeable of metabolites, reducing equivalents, and small molecules such as phosphate, and sulfate. Thus, mitochondrial shuttles and carriers function as the routes of influx and efflux of these metabolites and molecules across the inner membrane. The signal regulation of these shuttles and mitochondrial enzymes could play a key role in coordinating the mitochondrial metabolism to adapt the cytosolic part of metabolic pathways in liver metabolic stress. Intriguingly, the interaction of mitochondria protein SH3 domain-binding protein 5 (SAB/SH3BP5) and c-Jun N-terminal kinase (JNK) was found as a pivotal role in sustained activation of JNK and phosphorylated-JNK (P-JNK) mediated activation of lipogenic pathway in nutritional excess. Knockout or knockdown of SAB prevented or reversed the hepatic steatosis, inflammation, and fibrosis, and improved metabolic intolerance and energy expenditure. Moreover, blocking the SAB peptide prevents palmitic acid-induced P-JNK interaction with SAB and inhibition of mitochondrial bioenergetics, implying the P-JNK effect on mitochondrial metabolism. This review focuses on the flow of mitochondrial metabolites in metabolic stress conditions and the contribution of mitochondria and mitochondrial stress signals in hepatic steatosis.

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Triple negative breast cancer (TNBC) represents an aggressive disease associated with a high risk of recurrence after curative treatment and a poor prognosis in the metastatic setting. Chemotherapy was for years the only treatment available in the early and metastatic setting, due to the lack of actionable targets. Clinical practice has changed following the results obtained with the addition of immunotherapy to standard chemotherapy, the development of novel drugs [i.e. antibody-drug conjugates (ADCs)], and the use of targeted treatments for patients carrying germline pathogenic breast cancer susceptibility genes (BRCA) 1 or BRCA 2 variants. The treatment of early-stage disease has had a shift in clinical practice since July 2021, after the Food and Drug Administration (FDA) approval of pembrolizumab in association with chemotherapy as neoadjuvant treatment for TNBC and as a single agent in the subsequent adjuvant setting. This intensive treatment based on the combination of a poly-chemotherapy and an immune checkpoint inhibitor (ICI) led to the improvement of short- and long-term outcomes, but it has highlighted some new unmet clinical needs in the treatment of early-stage TNBC: the selection of the most effective adjuvant therapy and the integration of pembrolizumab with other therapeutic strategies [capecitabine, poly(ADP-ribose) polymerase (PARP) inhibitors] based on the achievement of pathologic complete response (pCR); the identification of predictive biomarkers to select patients who could most benefit from the addition of ICI, to minimize toxicities and to maximize outcomes; the possibility of de-escalating chemotherapy in favor of immune-combo or novel agents, such as ADCs; the role of immunotherapy in estrogen receptor (ER)-low patients. The advent of immunotherapy not only addresses current challenges in TNBC treatment but also holds the promise of a radical transformation in its therapeutic paradigm, enhancing significantly clinical outcomes and offering new perspectives for patients grappling with this aggressive form of breast cancer.

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Malignant tumors of the external auditory canal (EAC) are rare neoplasms that appear in the head and neck area. A common feature of these malignancies is their rarity, as well as their delayed diagnosis due to the appearance of non-specific symptoms that mimic various benign otologic conditions. The reported histological types of cancer of the external ear are: squamous cell carcinoma, basal cell carcinoma, malignant melanoma, Merkel cell carcinoma, angiosarcoma, adnexal carcinoma (including ceruminous adenocarcinoma and adenoid cystic carcinoma), and lymphoma (Lancet Oncol. 2005;6:411–20. doi: 10.1016/S1470-2045(05)70208-4). Several therapeutic interventions have been proposed, primarily orientated towards the cure of the patient, placing the surgical excision of the lesions at the tip of the spear. Subsequently and depending on the clinical stage and the pathological characteristics of the tumor, radiation, chemotherapy, a combination thereof, or some form of palliative treatment for particularly advanced cases, may be recommended. The aim of all the above-mentioned approaches is the complete resection of the mass with negative surgical margins along with lymph node dissection, the elimination of any residual disease or metastasis, and the improvement of survival. The anatomical complexity of the region will always remain a demanding challenge. Nevertheless, advances in the fields of ear microsurgery, imaging, radiation, molecular biology, and genomics have led to remarkable outcomes compared to the past, with a view to the patient’s quality of life. Large, well-organized, and prospective studies with the participation of multiple centers in contrast to existing retrospective studies with a limited number of patients will help to establish universally accepted guidelines. The exploration of the molecular and genetic background of these cancers in conjunction with the search for new biomarkers and target molecules seems promising for providing upgraded and more personalized treatment modalities for the future.

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In spite of the immense advancement in the diagnostic and treatment modalities, cancer continues to be one of the leading causes of mortality across the globe, responsible for the death of around 10 million patients every year. The foremost challenges faced in the treatment of this disease are chemoresistance, adverse effects of the drugs, and the high cost of treatment. Though scientific studies over the past few decades have foreseen and are focusing on the cancer-preventive and therapeutic potential of natural products and their underlying mechanism of action, many more of these agents are not still explored. Piperlongumine (PL), or piplartine, is one such alkaloid isolated from Piper longum Linn., which is shown to be safe and has significant potential in the prevention and therapy of cancer. Numerous shreds of evidence have established the ability of this alkaloid and its analogs and nanoformulations in modulating various complex molecular pathways such as phosphatidylinositol-3-kinase/protein kinase B/mammalian target of rapamycin, nuclear factor-kappa B, Janus kinases/signal transducer and activator of transcription 3, etc. and inhibit different hallmarks of cancer such as cell survival, proliferation, invasion, angiogenesis, epithelial-mesenchymal-transition, metastases, etc. In addition, PL was also shown to inhibit radioresistance and chemoresistance and sensitize the cancer cells to the standard chemotherapeutic agents. Therefore, this compound has high potential as a drug candidate for the prevention and treatment of different cancers. The current review briefly reiterates the anti-cancer properties of PL against different types of cancer, which permits further investigation by conducting clinical studies.

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The Raf kinase inhibitor protein (RKIP) has been reported to be underexpressed in many cancers and plays a role in the regulation of tumor cells' survival, proliferation, invasion, and metastasis, hence, a tumor suppressor. RKIP also regulates tumor cell resistance to cytotoxic drugs/cells. Likewise, the tumor suppressor, phosphatase and tensin homolog (PTEN), which inhibits the phosphatidylinositol 3 kinase (PI3K)/AKT pathway, is either mutated, underexpressed, or deleted in many cancers and shares with RKIP its anti-tumor properties and its regulation in resistance. The transcriptional and posttranscriptional regulations of RKIP and PTEN expressions and their roles in resistance were reviewed. The underlying mechanism of the interrelationship between the signaling expressions of RKIP and PTEN in cancer is not clear. Several pathways are regulated by RKIP and PTEN and the transcriptional and post-transcriptional regulations of RKIP and PTEN is significantly altered in cancers. In addition, RKIP and PTEN play a key role in the regulation of tumor cells response to chemotherapy and immunotherapy. In addition, molecular and bioinformatic data revealed crosstalk signaling networks that regulate the expressions of both RKIP and PTEN. These crosstalks involved the mitogen-activated protein kinase (MAPK)/PI3K pathways and the dysregulated nuclear factor-kappaB (NF-κB)/Snail/Yin Yang 1 (YY1)/RKIP/PTEN loop in many cancers. Furthermore, further bioinformatic analyses were performed to investigate the correlations (positive or negative) and the prognostic significance of the expressions of RKIP or PTEN in 31 different human cancers. These analyses were not uniform and only revealed that there was a positive correlation between the expression of RKIP and PTEN only in few cancers. These findings demonstrated the existence of signaling cross-talks between RKIP and PTEN and both regulate resistance. Targeting either RKIP or PTEN (alone or in combination with other therapies) may be sufficient to therapeutically inhibit tumor growth and reverse the tumor resistance to cytotoxic therapies.

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Cancer is the leading cause of mortality worldwide, which necessitates our consideration related to novel treatment approach. Tumor cells at the tumor microenvironment (TME), regulate a plethora of key mechanistic signaling pathways that obstruct antitumor immune responses by immune suppression, immune resistance or acquired immune tolerance. The present therapeutic regimes are provided independently or in combination, or as immunotherapies for cancer immune targeting. Immunotherapy has altered the arena of oncology and patient care. By using the host immune system, the immunostimulatory molecules can exert a robust, personalized response against the patient’s own tumors. Alternatively, tumors may exploit these strategies to escape immune recognition, and accordingly, such mechanisms represent chances for immunotherapy intervention. Nonetheless, despite promising outcomes from immunotherapies in recurrent and metastatic cancers, immune-therapeutics in clinics have been limited owing to unpredictability in the produced immune response and reported instances of immune-related adverse effects. The unrealized potential of immunotherapies in cancer management maybe due to the obstacles such as heterogeneous nature, multiple targets, patients’ immune response, specificity for cancer or variability in response generation in toxicity levels, delivery and cost related to therapeutics etc. Further revolutionary trends related to immunotherapies are noticeable with slower progress for cancer management. Recent advances in nanomedicine strategize to ameliorate the lacuna of immunotherapy as it relies on the inherent biophysical characteristics of nanocarriers: size, shape, surface charge and multifunctionality and exploiting them as first line therapy for delivery of biomolecules, single checkpoint inhibitors and for imaging of TME. Therefore, nano-assisted immunotherapies can boost the immunotherapeutic approach, overcoming factors that are with imminent potential risks related to it, thereby significantly improving the survival rate associated with it in cancer patients. Nanotechnology is anticipated to overcome the confines of existing cancer immunotherapy and to successfully combine various cancer treatment modes.

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