The ability to sustain unscheduled proliferation is a hallmark of cancer. The normal process of cell division occurs via the cell cycle, a series of highly regulated steps that are orchestrated at the molecular level by specific cyclins that act in association with cyclin-dependent kinases (CDKs). Cyclin D and CDK4/6 play a key role in cell-cycle progression by phosphorylating and inactivating the retinoblastoma protein, a tumor suppressor that restrains G1- to S-phase progression. The first-generation CDK inhibitors demonstrated broad activity upon several CDKs, which likely explains their considerable toxicities and limited efficacy. Palbociclib, ribociclib, and abemaciclib represent a new class of highly specific ATP-competitive CDK4/6 inhibitors that induce reversible G1-phase cell-cycle arrest in retinoblastoma-positive tumor models. Both palbociclib and ribociclib have been approved in combination with hormone-based therapy for the treatment of naïve hormone receptor-positive advanced breast cancer on the basis of an improvement in progression-free survival. In general, CDK4/6 inhibitors are cytostatic as monotherapy but demonstrate favorable tolerability, which has prompted interest in combination approaches. Combinations with phosphatidylinositol 3-kinase and mammalian target of rapamycin inhibitors in breast cancer, and inhibitors of the RAS/RAF/mitogen-activated protein kinase pathway in RAS-mutant cancers are particularly promising approaches that are currently being evaluated. Although the subject of intense preclinical study, predictive biomarkers for response and resistance to these drugs remain largely undefined. CDK4/6 inhibitors have emerged as the most promising of the cell-cycle therapeutics and intense efforts are now underway to expand the reach of this paradigm.
Purpose: This phase I study assessed the safety, pharmacokinetics (PKs), and efficacy of MIW815 (ADU-S100), a novel synthetic cyclic dinucleotide that activates the stimulator of IFN genes (STING) pathway, in patients with advanced/metastatic cancers. Patients and Methods: Patients (n = 47) received weekly i.t. injections of MIW815, 50 to 6,400 μg, on a 3-weeks-on/1-week-off schedule. Results: A maximum tolerated dose was not reached. Most common treatment-related adverse events were pyrexia (17%), chills, and injection-site pain (each 15%). MIW815 was rapidly absorbed from the injection site with dose-proportional PK, a rapid terminal plasma half-life (approximately 24 minutes), and high interindividual variability. One patient had a partial response (PR; Merkel cell carcinoma); two patients had unconfirmed PR (parotid cancer, myxofibrosarcoma). Lesion size was stable or decreased in 94% of evaluable, injected lesions. RNA expression and immune infiltration assessments in paired tumor biopsies did not reveal significant on-treatment changes. However, increases in inflammatory cytokines and peripheral blood T-cell clonal expansion suggested systemic immune activation. Conclusions: MIW815 was well tolerated in patients with advanced/metastatic cancers. Clinical activity of single-agent MIW815 was limited in this first-in-human study; however, evidence of systemic immune activation was seen.
Soft tissue and bone sarcomas are malignancies of mesenchymal origin, and more than 50 subtypes are defined. For most sarcomas, locally advanced or unresectable disease is still treated with cytotoxic chemotherapy. Recently, our understanding of subtype-specific cancer biology has expanded, and it has revealed distinct molecular alterations responsible for tumor initiation and progression. These findings have motivated the development of targeted therapies that are being evaluated in subtype-specific or biomarker-driven clinical trials. Indeed, the spectrum of targeted drug development in sarcoma now spans many of the most active paradigms in cancer research and includes agents that target cancer-related vulnerabilities in receptor tyrosine kinases and intracellular signaling pathways, epigenetics, metabolism, nuclear-cytoplasmic transport, and many others. Our understanding of the sarcoma immune microenvironment and heterogeneous mechanisms of tumor immune evasion has also expanded. Although a subset of sarcomas appears inflamed and responsive to immune checkpoint blockade with programmed death 1 (PD-1) targeted agents, novel immunotherapies and combinations likely will be needed for most subtypes. A variety of approaches-including targeting immune checkpoints other than PD-1; modulating tumor-associated macrophage phenotype from tumor-promoting to tumor-suppressive status; using cellular-based therapies, such as chimeric antigen and high-affinity T-cell receptors to deepen the adaptive immune response; and reinvigorating older approaches, such as vaccines and oncolytic virus-based treatments-are being investigated. The goal of these new approaches is to harness subtype-specific insights into cancer and immune biology to bring more effective and less toxic treatments to the clinic for the benefit of patients with sarcoma.
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