Thyroid cancer comprises different clinical and histological entities. Whereas differentiated (DTCs) malignancies are sensitive to radioiodine therapy, anaplastic (ATCs) and medullary (MTCs) tumors do not uptake radioactive iodine and display aggressive features associated with a poor prognosis. Moreover, in a majority of DTCs, disease evolution leads to the progressive loss of iodine sensitivity. Hence, iodine-refractory DTCs, along with ATCs and MTCs, require alternative treatments reflective of their different tumor biology. In the last decade, the molecular mechanisms promoting thyroid cancer development and progression have been extensively studied. This has led to a better understanding of the genomic landscape, displayed by thyroid malignancies, and to the identification of novel therapeutic targets. Indeed, several pharmacological compounds have been developed for iodine-refractory tumors, with four multi-target tyrosine kinase inhibitors already available for DTCs (sorafenib and lenvatinib) and MTCs (cabozantib and vandetanib), and a plethora of drugs currently being evaluated in clinical trials. In this review, we will describe the genomic alterations and biological processes intertwined with thyroid cancer development, also providing a thorough overview of targeted drugs already tested or under investigation for these tumors. Furthermore, given the existing preclinical evidence, we will briefly discuss the potential role of immunotherapy as an additional therapeutic strategy for the treatment of thyroid cancer.

Obesity is a strong risk factor for cancer progression, posing obesity-related cancer as one of the leading causes of death. Nevertheless, the molecular mechanisms that endow cancer cells with metastatic properties in patients affected by obesity remain unexplored.Here, we show that IL-6 and HGF, secreted by tumor neighboring visceral adipose stromal cells (V-ASCs), expand the metastatic colorectal (CR) cancer cell compartment (CD44v6 + ), which in turn secretes neurotrophins such as NGF and NT-3, and recruits adipose stem cells within tumor mass. Visceral adipose-derived factors promote vasculogenesis and the onset of metastatic dissemination by activation of STAT3, which inhibits miR-200a and enhances ZEB2 expression, effectively reprogramming CRC cells into a highly metastatic phenotype. Notably, obesity-associated tumor microenvironment provokes a transition in the transcriptomic expression profile of cells derived from the epithelial consensus molecular subtype (CMS2) CRC patients towards a mesenchymal subtype (CMS4). STAT3 pathway inhibition reduces ZEB2 expression and abrogates the metastatic growth sustained by adipose-released proteins. Together, our data suggest that targeting adipose factors in colorectal cancer patients with obesity may represent a therapeutic strategy for preventing metastatic disease.

The Insulin-like growth factor (IGF) axis is one of the best-established drivers of thyroid transformation, as thyroid cancer cells overexpress both IGF ligands and their receptors. Thyroid neoplasms encompass distinct clinical and biological entities as differentiated thyroid carcinomas (DTC)—comprising papillary (PTC) and follicular (FTC) tumors—respond to radioiodine therapy, while undifferentiated tumors—including poorly-differentiated (PDTC) or anaplastic thyroid carcinomas (ATCs)—are refractory to radioactive iodine and exhibit limited responses to chemotherapy. Thus, safe and effective treatments for the latter aggressive thyroid tumors are urgently needed. Despite a strong preclinical rationale for targeting the IGF axis in thyroid cancer, the results of the available clinical studies have been disappointing, possibly because of the crosstalk between IGF signaling and other pathways that may result in resistance to targeted agents aimed against individual components of these complex signaling networks. Based on these observations, the combinations between IGF-signaling inhibitors and other anti-tumor drugs, such as DNA damaging agents or kinase inhibitors, may represent a promising therapeutic strategy for undifferentiated thyroid carcinomas. In this review, we discuss the role of the IGF axis in thyroid tumorigenesis and also provide an update on the current knowledge of IGF-targeted combination therapies for thyroid cancer.

Human trophoblast cell-surface antigen-2 (Trop-2) is a membrane glycoprotein involved in cell proliferation and motility, frequently overexpressed in epithelial tumors. Thus, it represents an attractive target for anticancer therapies. Sacituzumab govitecan (SG) is a third-generation antibody-drug conjugate, consisting of an anti-Trop-2 monoclonal antibody (hRS7), a hydrolyzable linker, and a cytotoxin (SN38), which inhibits topoisomerase 1. Specific pharmacological features, such as the high antibody to payload ratio, the ultra-toxic nature of SN38, and the capacity to kill surrounding tumor cells (the bystander effect), make SG a very promising drug for cancer treatment. Indeed, unprecedented results have been observed with SG in patients with heavily pretreated advanced triple-negative breast cancer and urothelial carcinomas, and the drug has already received approval for these indications. These results are coupled with a manageable toxicity profile, with neutropenia and diarrhea as the most frequent adverse events, mainly of grades 1–2. While several trials are exploring SG activity in different tumor types and settings, potential biomarkers of response are under investigation. Among these, Trop-2 overexpression and the presence of BRCA1/2 mutations seem to be the most promising. We review the available literature concerning SG, with a focus on its toxicity spectrum and possible biomarkers of its response.

Background: Adherence to oral anticancer therapies among breast cancer patients is an often-overlooked issue. A lack of patient compliance can be caused by several factors, and may hinder the efficacy of prescribed medication, leading to a shorter than expected survival. In this context, few data about adherence to CDK4/6 inhibitors in real-world practice are available. We report here the results of a retrospective analysis of adherence to abemaciclib plus endocrine therapy in a cohort of women with hormone receptor-positive (HR+), epidermal growth factor 2 negative (HER2−) breast cancer. Methods: Abemaciclib adherence was computed as the ratio between the total number of cycles/months that medication was supplied and the months between the first and the last prescription. The proportion of Days Covered (PDC) ranged from 0 to 1. A score of 0.8 (i.e., 80% adherence rate) was the cutoff used to classify the patients as adherent (0.8 ≤ PDC ≤ 1) or non-adherent (0 ≤ PDC < 0.8). The received dose intensity was also calculated. Results: The abemaciclib pharmacy claims of 100 women with HR+/HER2− breast cancer were retrieved. Most patients (91%) were treated in the advanced setting. Abemaciclib was more frequently taken with an aromatase inhibitor (63%) than with fulvestrant (27%). In this population, the adherence rate was high (92.25% + 1.939 SD). The proportion of non-adherent patients taking abemaciclib with PDC <0.8 was 12%. There was a significative correlation between the occurrence of side effects and the use of <5 drugs for non-oncological illnesses, probably reflecting concomitant non-oncological diseases. Conclusions: Adherence to abemaciclib-based therapy is high in a real-life setting, pending the adequate and proactive management of patients. The careful evaluation of patients and detailed information about expected adverse events are essential to ensure adherence to this antineoplastic agent.

Background. In recent years, the role of prostate-specific membrane antigen (PSMA) in the imaging and treatment of prostate cancer (PCa) has been extensively investigated. However, despite its name, PSMA is not exclusively specific to PCa. It has been found to be expressed in the neo-vasculature of various solid tumors, including breast cancer (BC), in which it is associated with tumor angiogenesis. Methods. This review aims to assess the potential of PSMA-based radiopharmaceuticals for BC diagnosis and treatment. It explores the current landscape by analyzing preclinical and clinical studies, as well as ongoing clinical trials, to provide insights into the PSMA-targeted approaches in BC management. Results. Early studies suggest PSMA-based imaging could improve BC lesion detection, especially in TNBC. The available data remains too preliminary to conclusively assess whether PSMA-based imaging or therapy will offer a significant advantage in BC. However, some preclinical findings suggest that this approach may hold promise as a novel strategy for managing this widespread malignancy. Conclusions. PSMA-based strategies show potential for BC diagnosis and treatment, but further research is needed. Ongoing and future clinical trials are expected to provide deeper insights into the potential utility of this approach.