Recent Advances in Anticancer Strategies

The “Warburg effect” consists of a metabolic shift in energy production from oxidative phosphorylation to glycolysis. The continuous activation of glycolysis in cancer cells causes rapid energy production and an increase in lactate, leading to the acidification of the tumour microenvironment, chemo- and radioresistance, as well as poor patient survival. Nevertheless, the mitochondrial metabolism can be also involved in aggressive cancer characteristics. The metabolic differences between cancer and normal tissues can be considered the Achilles heel of cancer, offering a strategy for new therapies. One of the main causes of treatment resistance consists of the increased expression of efflux pumps, and multidrug resistance (MDR) proteins, which are able to export chemotherapeutics out of the cell. Cells expressing MDR proteins require ATP to mediate the efflux of their drug substrates. Thus, inhibition of the main energy-producing pathways in cancer cells, not only induces cancer cell death per se, but also overcomes multidrug resistance. Given that most anticancer drugs do not have the ability to distinguish normal cells from cancer cells, a number of drug delivery systems have been developed. These nanodrug delivery systems provide flexible and effective methods to overcome MDR by facilitating cellular uptake, increasing drug accumulation, reducing drug efflux, improving targeted drug delivery, co-administering synergistic agents, and increasing the half-life of drugs in circulation. Full article

Tumor neoantigens are widely used in cancer immunotherapy, and a growing body of research suggests that microbes play an important role in these neoantigen-based immunotherapeutic processes. The human body and its surrounding environment are filled with a large number of microbes that are in long-term interaction with the organism. The microbiota can modulate our immune system, help activate neoantigen-reactive T cells, and play a great role in the process of targeting tumor neoantigens for therapy. Recent studies have revealed the interconnection between microbes and neoantigens, which can cross-react with each other through molecular mimicry, providing theoretical guidance for more relevant studies. The current applications of microbes in immunotherapy against tumor neoantigens are mainly focused on cancer vaccine development and immunotherapy with immune checkpoint inhibitors. This article summarizes the related fields and suggests the importance of microbes in immunotherapy against neoantigens. Full article

Medulloblastoma is the most common malignant pediatric brain tumor and is associated with significant morbidity and mortality in the pediatric population. Despite the use of multiple therapeutic approaches consisting of surgical resection, craniospinal irradiation, and multiagent chemotherapy, the prognosis of many patients with medulloblastoma remains dismal. Additionally, the high doses of radiation and the chemotherapeutic agents used are associated with significant short- and long-term complications and adverse effects, most notably neurocognitive delay. Hence, there is an urgent need for the development and clinical integration of targeted treatment regimens with greater efficacy and superior safety profiles. Since the adoption of the molecular-based classification of medulloblastoma into wingless (WNT) activated, sonic hedgehog (SHH) activated, group 3, and group 4, research efforts have been directed towards unraveling the genetic, epigenetic, transcriptomic, and proteomic profiles of each subtype. This review aims to delineate the progress that has been made in characterizing the neurodevelopmental and molecular features of each medulloblastoma subtype. It further delves into the implications that these characteristics have on the development of subgroup-specific targeted therapeutic agents. Furthermore, it highlights potential future avenues for combining multiple agents or strategies in order to obtain augmented effects and evade the development of treatment resistance in tumors. Full article

Radiotherapy (RT) using ultra-high dose rate (UHDR) radiation, known as FLASH RT, has shown promising results in reducing normal tissue toxicity while maintaining tumor control. However, implementing FLASH RT in clinical settings presents technical challenges, including limited depth penetration and complex treatment planning. Monte Carlo (MC) simulation is a valuable tool for dose calculation in RT and has been investigated for optimizing FLASH RT. Various MC codes, such as EGSnrc, DOSXYZnrc, and Geant4, have been used to simulate dose distributions and optimize treatment plans. Accurate dosimetry is essential for FLASH RT, and radiation detectors play a crucial role in measuring dose delivery. Solid-state detectors, including diamond detectors such as microDiamond, have demonstrated linear responses and good agreement with reference detectors in UHDR and ultra-high dose per pulse (UHDPP) ranges. Ionization chambers are commonly used for dose measurement, and advancements have been made to address their response nonlinearities at UHDPP. Studies have proposed new calculation methods and empirical models for ion recombination in ionization chambers to improve their accuracy in FLASH RT. Additionally, strip-segmented ionization chamber arrays have shown potential for the experimental measurement of dose rate distribution in proton pencil beam scanning. Radiochromic films, such as Gafchromic^TM EBT3, have been used for absolute dose measurement and to validate MC simulation results in high-energy X-rays, triggering the FLASH effect. These films have been utilized to characterize ionization chambers and measure off-axis and depth dose distributions in FLASH RT. In conclusion, MC simulation provides accurate dose calculation and optimization for FLASH RT, while radiation detectors, including diamond detectors, ionization chambers, and radiochromic films, offer valuable tools for dosimetry in UHDR environments. Further research is needed to refine treatment planning techniques and improve detector performance to facilitate the widespread implementation of FLASH RT, potentially revolutionizing cancer treatment. Full article