PARP1 Characterization as a Potential Biomarker for BCR::ABL1 p190+ Acute Lymphoblastic Leukemia.

Detection of t(9;22), and consequent BCR::ABL1 fusion, is still a marker of worse prognosis for acute lymphoblastic leukemia (ALL), with resistance to tyrosine-kinase inhibitor therapy being a major obstacle in the clinical practice for this subset of patients. In this study, we investigated the effectiveness of targeting poly-ADP-ribose polymerase (PARP) in a model of BCR::ABL1 p190+ ALL, the most common isoform to afflict ALL patients, and demonstrated the use of experimental PARP inhibitor (PARPi), AZD2461, as a therapeutic option with cytotoxic capabilities similar to that of imatinib, the current gold standard in medical care. We characterized cytostatic profiles, induced cell death, and biomarker expression modulation utilizing cell models, also providing a comprehensive genome-wide analysis through an aCGH of the model used, and further validated PARP1 differential expression in samples of ALL p190+ patients from local healthcare institutions, as well as in larger cohorts of online and readily available datasets. Overall, we demonstrate the effectiveness of PARPi in the treatment of BCR::ABL1 p190+ ALL cell models and that PARP1 is differentially expressed in patient samples. We hope our findings help expand the characterization of molecular profiles in ALL settings and guide future investigations into novel biomarker detection and pharmacological choices in clinical practice.

Genome Editing for Engineering the Next Generation of Advanced Immune Cell Therapies.

Our current genetic engineering capacity through synthetic biology and genome editing is the foundation of a revolution in biomedical science: the use of genetically programmed cells as therapeutics. The prime example of this paradigm is the adoptive transfer of genetically engineered T cells to express tumor-specific receptors, such as chimeric antigen receptors (CARs) or engineered T-cell receptors (TCR). This approach has led to unprecedented complete remission rates in patients with otherwise incurable hematological malignancies. However, this approach is still largely ineffective against solid tumors, which comprise the vast majority of neoplasms. Also, limitations associated with the autologous nature of this therapy and shared markers between cancer cells and T cells further restrict the access to these therapies. Here, we described how cutting-edge genome editing approaches have been applied to unlock the full potential of these revolutionary therapies, thereby increasing therapeutic efficacy and patient accessibility.

Hybrid lipid-biopolymer nanocarrier as a strategy for GBM photodynamic therapy (PDT).

Glioblastoma (GBM) is the most common brain cancer characterized by aggressive and infiltrated tumors. For this, hybrid biopolymer-lipid nanoparticles coated with biopolymers such as chitosan and lipidic nanocarriers (LN) loaded with a photosensitizer (AlClPc) can be used for GBM photodynamic therapy. The chitosan-coated LN exhibited stable physicochemical characteristics and presented as an excellent lipid nanocarrier with highly efficiently encapsulated photosensitizer chloro-aluminum phthalocyanine (AlClPc). LN(AlClPc)Ct0.1% in the presence of light produced more reactive oxygen species and reduced brain tumor cell viability and proliferation. Confirm the effects of in vivo LN applications with photodynamic therapy confirmed that the total brain tumor area decreased without systemic toxicity in mice. These results suggest a promising strategy for future clinical applications to improve brain cancer treatment.

Strategies to Enhance the Therapeutic Efficacy, Applicability, and Safety of Genetically Engineered Immune Cells.

The field of cell therapy is leading a paradigm shift in drug development. The recent convergence of several fields, including immunology, genetics, and synthetic biology, now allows for the introduction of artificial receptors and the design of entire genetic circuitries to finely program the behavior of injected cells. A prime example of these next-generation living drugs comes in the form of T cells expressing chimeric antigen receptors (CARs), which have already demonstrated definitive evidence of therapeutic efficacy against some hematological malignancies. However, several obstacles still restrict the antitumor efficacy of and impair the widespread use of CAR-T cells. Critical challenges include limited persistence and antitumor activity in vivo, antigen escape, scarcity of suitable single markers for targeting, and therapy-related toxicity. Nevertheless, intense research activity in this field has resulted in a plethora of creative solutions to address each of these limitations. In this review, we provide a comprehensive snapshot of the current strategies used to enhance the therapeutic efficacy, applicability, and safety of genetically engineered immune cells to treat cancer.