RESUMO
T-prolymphocytic leukemia (T-PLL) is a mature T-cell neoplasm associated with marked chemotherapy resistance and continued poor clinical outcomes. Current treatments, i.e. the CD52-antibody alemtuzumab, offer transient responses, with relapses being almost inevitable without consolidating allogeneic transplantation. Recent more detailed concepts of T-PLL's pathobiology fostered the identification of actionable vulnerabilities: (i) altered epigenetics, (ii) defective DNA damage responses, (iii) aberrant cell-cycle regulation, and (iv) deregulated pro-survival pathways, including TCR and JAK/STAT signaling. To further develop related pre-clinical therapeutic concepts, we studied inhibitors of (H)DACs, BCL2, CDK, MDM2, and clas-sical cytostatics, utilizing (a) single-agent and combinatorial compound testing in 20 well-characterized and molecularly-profiled primary T-PLL (validated by additional 42 cases), and (b) 2 independent murine models (syngeneic transplants and patient-derived xenografts). Overall, the most efficient/selective single-agents and combinations (in vitro and in mice) in-cluded Cladribine, Romidepsin ((H)DAC), Venetoclax (BCL2), and/or Idasanutlin (MDM2). Cladribine sensitivity correlated with expression of its target RRM2. T-PLL cells revealed low overall apoptotic priming with heterogeneous dependencies on BCL2 proteins. In additional 38 T-cell leukemia/lymphoma lines, TP53 mutations were associated with resistance towards MDM2 inhibitors. P53 of T-PLL cells, predominantly in wild-type configuration, was amenable to MDM2 inhibition, which increased its MDM2-unbound fraction. This facilitated P53 activa-tion and down-stream signals (including enhanced accessibility of target-gene chromatin re-gions), in particular synergy with insults by Cladribine. Our data emphasize the therapeutic potential of pharmacologic strategies to reinstate P53-mediated apoptotic responses. The identified efficacies and their synergies provide an informative background on compound and patient selection for trial designs in T-PLL.
RESUMO
The discovery of Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) and CRISPR-associated protein 9 (Cas9) technology has revolutionized field of cancer treatment. This review explores usage of CRISPR/Cas9 for editing and investigating genes involved in human carcinogenesis. It provides insights into the development of CRISPR as a genetic tool. Also, it explores recent developments and tools available in designing CRISPR/Cas9 systems for targeting oncogenic genes for cancer treatment. Further, we delve into an overview of cancer biology, highlighting key genetic alterations and signaling pathways whose deletion prevents malignancies. This fundamental knowledge enables a deeper understanding of how CRISPR/Cas9 can be tailored to address specific genetic aberrations and offer personalized therapeutic approaches. In this review, we showcase studies and preclinical trials that show the utility of CRISPR/Cas9 in disrupting oncogenic targets, modulating tumor microenvironment and increasing the efficiency of available anti treatments. It also provides insight into the use of CRISPR high throughput screens for cancer biomarker identifications and CRISPR based screening for drug discovery. In conclusion, this review offers an overview of exciting developments in engineering CRISPR/Cas9 therapeutics for cancer treatment and highlights the transformative potential of CRISPR for innovation and effective cancer treatments.
RESUMO
The infrastructure needed to detect Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection (COVID-19) that complies completely with WHO guidelines is lacking across many parts of the globe, especially in developing countries, including Nepal. We outline the problems faced by such countries and suggest that the national and international community should collaborate in the development and adoption of novel protocols for the rapid detection of COVID-19 according to locally available infrastructure, in order to fight against the outbreak.