Tyrosine Kinase Receptors in Oncology Esteban-Villarrubia, Jorge; Soto-Castillo, Juan José; Pozas, Javier ...
International journal of molecular sciences,
11/2020, Letnik:
21, Številka:
22
Journal Article
Recenzirano
Odprti dostop
Tyrosine kinase receptors (TKR) comprise more than 60 molecules that play an essential role in the molecular pathways, leading to cell survival and differentiation. Consequently, genetic alterations ...of TKRs may lead to tumorigenesis and, therefore, cancer development. The discovery and improvement of tyrosine kinase inhibitors (TKI) against TKRs have entailed an important step in the knowledge-expansion of tumor physiopathology as well as an improvement in the cancer treatment based on molecular alterations over many tumor types. The purpose of this review is to provide a comprehensive review of the different families of TKRs and their role in the expansion of tumor cells and how TKIs can stop these pathways to tumorigenesis, in combination or not with other therapies. The increasing growth of this landscape is driving us to strengthen the development of precision oncology with clinical trials based on molecular-based therapy over a histology-based one, with promising preliminary results.
Despite being infrequent tumors, the incidence and prevalence of pancreatic neuroendocrine tumors (P-NETs) has been rising over the past few decades. In recent years, rigorous phase III clinical ...trials have been conducted, allowing the approval of several drugs that have become the standard of care in these patients. Although various treatments are used in clinical practice, including somatostatin analogues (SSAs), biological therapies like sunitinib or everolimus, peptide receptor radionuclide therapy (PRRT) or even chemotherapy, a consensus regarding the optimal sequence of treatment has not yet been reached. Notwithstanding, sunitinib is largely used in these patients after the promising results shown in SUN111 phase III clinical trial. However, both prompt progression as well as tumor recurrence after initial response have been reported, suggesting the existence of primary and acquired resistances to this antiangiogenic drug. In this review, we aim to summarize the most relevant mechanisms of angiogenesis resistance that are key contributors of tumor progression and dissemination. Furthermore, several targeted molecules acting selectively against these pathways have shown promising results in preclinical models, and preliminary results from ongoing clinical trials are awaited.
Colon cancer is one of the most frequently diagnosed malignancies in adults, considering both its incidence and prevalence. Anatomically, the right colon is considered as being from the cecum to the ...splenic flexure, and the left colon is from the splenic flexure to the rectum. Sidedness is a surrogate of a wide spectrum of colorectal cancer (CRC) biology features (embryology, microbiome, methylation, microsatellite instability (MSI), BRAF, aging, KRAS, consensus molecular subtypes (CMS), etc.), which result in prognostic factors. Different molecular subtypes have been identified, according to genomic and transcriptomic criteria. A subgroup harboring a BRAF mutation has been described, and represents approximately 10% of the patients diagnosed with colon cancer. This subgroup has morphological, clinical, and therapeutic characteristics that differ substantially from patients who do not carry this genetic alteration. Unfortunately, there is no established standard of care for this particular cohort of patients. This manuscript aims to study the biology of this subgroup of colon cancer, to understand the current approach in clinical research.
Bone sarcomas are a heterogeneous group of rare tumors with a predominance in the young population. Few options of systemic treatment are available once they become unresectable and resistant to ...conventional chemotherapy. A better knowledge of the key role that tyrosine kinase receptors (VEGFR, RET, MET, AXL, PDGFR, KIT, FGFR, IGF-1R) may play in the pathogenesis of these tumors has led to the development of multi-target inhibitors (TKIs) that are progressively being incorporated into our therapeutic arsenal. Osteosarcoma (OS) is the most frequent primary bone tumor and several TKIs have demonstrated clinical benefit in phase II clinical trials (cabozantinib, regorafenib, apatinib, sorafenib, and lenvatinib). Although the development of TKIs for other primary bone tumors is less advanced, preclinical data and early trials have begun to show their potential benefit in advanced Ewing sarcoma (ES) and rarer bone tumors (chondrosarcoma, chordoma, giant cell tumor of bone, and undifferentiated pleomorphic sarcoma). Previous reviews have mainly provided information on TKIs for OS and ES. We aim to summarize the existing knowledge regarding the use of TKIs in all bone sarcomas including the most recent studies as well as the potential synergistic effects of their combination with other systemic therapies.
Metastatic urothelial cancer, associated with a poor prognosis, is still major cause of cancer-related death, with scarce options of effective treatment after progression to platinum-based ...chemotherapy and immunotherapy. The human epithelial growth factor receptor 2 (Her-2) has been identified as a new therapeutic target in medical oncology. However, despite the encouraging results in breast and gastric cancers, clinical trials with anti-Her-2 monoclonal antibodies and tyrosine-kinase inhibitors have shown limited efficacy of this strategy in urothelial tumors. Notably, more favorable data have been recently shown that antibody-drug conjugates are currently emerging as a novel promising approach for Her-2 targeted therapy in advanced urothelial cancer.
PARP inhibitors are progressively becoming a part of our therapeutic arsenal against BRCA-defective tumors, because of their capacity to induce synthetic lethality in cells with a deficiency in the ...homologous recombination repair system. Olaparib and talazoparib have been approved for metastatic breast cancer in carriers of germline BRCA mutations, which are found in approximately 6% of patients with breast cancer. We report the case of a patient with metastatic breast cancer, carrier of a germline mutation in BRCA2, with a complete response to first-line treatment with talazoparib, maintained after 6 years. To the best of our knowledge, this is the longest response reported with a PARP inhibitor in a BRCA-mutated tumor. We have made a review of literature, regarding the rationale for PARP inhibitors in carriers of BRCA mutations and their clinical relevance in the management of advanced breast cancer, as well as their emerging role in early stage disease, alone and in combination with other systemic therapies.
There is substantial heterogeneity between different subtypes of sarcoma regarding their biological behavior and microenvironment, which impacts their responsiveness to immunotherapy. Alveolar ...soft-part sarcoma, synovial sarcoma and undifferentiated pleomorphic sarcoma show higher immunogenicity and better responses to checkpoint inhibitors. Combination strategies adding immunotherapy to chemotherapy and/or tyrosine-kinase inhibitors globally seem superior to single-agent schemes. Therapeutic vaccines and different forms of adoptive cell therapy, mainly engineered TCRs, CAR-T cells and TIL therapy, are emerging as new forms of immunotherapy for advanced solid tumors. Tumor lymphocytic infiltration and other prognostic and predictive biomarkers are under research.
Adoptive cell therapy (ACT) comprises different strategies to enhance the activity of T lymphocytes and other effector cells that orchestrate the antitumor immune response, including chimeric antigen ...receptor (CAR) T-cell therapy, T-cell receptor (TCR) gene-modified T cells, and therapy with tumor-infiltrating lymphocytes (TILs). The outstanding results of CAR-T cells in some hematologic malignancies have launched the investigation of ACT in patients with refractory solid malignancies. However, certain characteristics of solid tumors, such as their antigenic heterogeneity and immunosuppressive microenvironment, hamper the efficacy of antigen-targeted treatments. Other ACT modalities, such as TIL therapy, have emerged as promising new strategies. TIL therapy has shown safety and promising activity in certain immunogenic cancers, mainly advanced melanoma, with an exciting rationale for its combination with immune checkpoint inhibitors. However, the implementation of TIL therapy in clinical practice is hindered by several biological, logistic, and economic challenges. In this review, we aim to summarize the current knowledge, available clinical results, and potential areas of future research regarding the use of T cell therapy in patients with solid tumors.
Metastatic colorectal cancer (mCRC) with mutated BRAF exhibits distinct biological and molecular features that set it apart from other subtypes of CRC. Current standard treatment for these tumors ...involves a combination of chemotherapy (CT) and VEGF inhibitors. Recently, targeted therapy against BRAF and immunotherapy (IT) for cases with microsatellite instability (MSI) have been integrated into clinical practice. While targeted therapy has shown promising results, resistance to treatment eventually develops in a significant portion of responsive patients. This article aims to review the available literature on mechanisms of resistance to BRAF inhibitors (BRAFis) and potential therapeutic strategies to overcome them.
•Σ17PCDD/Fs were analyzed for the first time in HCH wastes sampled in the Bailín landfill, Spain.•Landfill leachates, soil, sediments and DNAPLs were also characterized in terms of ...Σ17PCDD/Fs.•Maximum Σ17PCDD/Fs (387,000ng·L−1) was found in the DNAPL waste, WHO-TEQ 37,353ng·L−1.•Dioxins formation during lindane manufacturing has been evidenced.
Lindane (γ-hexachlorocyclohexane) manufacture in Spain generated nearly 200,000tonnes of HCH wastes; near 160,000tonnes were originated by the Inquinosa factory located in Sabiñánigo (northern Spain) and were deposited in unlined landfill sites. This study reports for the first time the content of polychlorinated dibenzo-p-dioxin/dibenzofuran (PCDD/Fs) in non-recycled HCH wastes that had been disposed in the Bailín landfill site in Sabiñánigo. Samples from solid HCH powder residues (white HCH and δ-paste wastes) and the dense non-aqueous phase liquids (DNAPLs), as well as landfill leachates, soil and sediments have been characterized. White HCH wastes exhibited a toxicity of 1488ngWHO-TEQ2005·kg−1 (Σ17 PCDD/Fs), while δ-paste wastes presented a noticeable higher toxicity (12,094ngWHO-TEQ2005·kg−1). Nevertheless, the maximum toxicity value was found for DNAPLs (37,353ngWHO-TEQ2005·L−1). Dioxins were predominant in the DNAPL waste whereas furans predominated in the landfill leachates, soil and sediments. However, in solid HCH wastes, PCDD and PCDFs contributed in a similar proportion. The PCDD/Fs congener profiles in landfill leachates, soil and sediments do not resemble the PCDD/Fs profiles found for the HCH wastes. These preliminary results will be of paramount importance in order to estimate the total quantities of PCDD/Fs disposed to the landfill site and to assess the potential mobility of PCDD/Fs, especially to groundwater and landfill leachates. Besides, this information is of great value to design periodical monitoring plans to evaluate the presence of PCDD/Fs in the impacted groundwater and leachates and finally, to evaluate the risk of PCDD/Fs for the environment and human health.
Display omitted
PDF
