The cancer stem cell (SC) theory proposes that a population of SCs serves as the driving force behind fundamental tumor processes, including metastasis, recurrence, and resistance to therapy. The standard of care for patients with stage III and high-risk stage II colorectal cancer (CRC) includes surgery and adjuvant chemotherapy. Fluoropyrimidines and their combination with oxaliplatin increased the cure rates, being able to eradicate the occult metastatic SC in a fraction of patients. The treatment for unresectable metastatic CRC is based on chemotherapy, antibodies to VEGF and EGFR, and tyrosine-kinase inhibitors. Immunotherapy is used in MSI-H tumors. Currently used drugs target dividing cells and, while often effective at debulking tumor mass, these agents have largely failed to cure metastatic disease. SCs are generated either due to genetic and epigenetic alterations in stem/progenitor cells or to the dedifferentiation of somatic cells where diverse signaling pathways such as Wnt/β-catenin, Hedgehog, Notch, TGF-β/SMAD, PI3K/Akt/mTOR, NF-κB, JAK/STAT, DNA damage response, and Hippo-YAP play a key role. Anti-neoplastic treatments could be improved by elimination of SCs, becoming an attractive target for the design of novel agents. Here, we present a review of clinical trials assessing the efficacy of targeted treatment focusing on these pathways in CRC.

Colorectal cancer (CRC) is the third most common cancer worldwide. The standard treatment in locally advanced rectal cancer is preoperative radiation alone or in combination with chemotherapy, followed by adjuvant chemotherapy. Rectal cancer is highly lethal, with only 20% of patients showing a complete remission (by RECIST) after standard treatment, although they commonly show local or systemic relapse likely due to its late detection and high chemotherapy resistance, among other reasons. Here, we explored the role of PAI1 (Serpin E1) in rectal cancer through the analyses of public patient databases, our own cohort of locally advanced rectal cancer patients and a panel of CRC cell lines. We showed that PAI1 expression is upregulated in rectal tumors, which is associated with decreased overall survival and increased metastasis and invasion in advanced rectal tumors. Accordingly, PAI1 expression is correlated with the expression of (Epithelial-to-Mesenchymal Transition) EMT-associated genes and genes encoding drug targets, including the tyrosine kinases PDGFRb, PDGFRa and FYN, the serine/threonine kinase PIM1 and BRAF. In addition, we demonstrate that cells expressing PAI1 protein are more sensitive to the PIM inhibitor AZD1208, suggesting that PAI1 could be used to predict response to treatment with PIM inhibitors and to complement radiotherapy in rectal tumors.

Purpose: CB307 is a trispecific variable heavy-chain antibody fragment against prostate-specific membrane antigen (PSMA), CD137, and human serum albumin. It is designed to mitigate hepatotoxicity by activating T cells only in PSMA-positive tumors and to increase drug half-life through albumin binding. This phase I study investigated the safety and tolerability of CB307 as monotherapy or in combination with pembrolizumab. Patients and Methods: Patients who were heavily pretreated with PSMA-positive solid tumors were enrolled in the dose-escalation phase of CB307 monotherapy. The additional safety and efficacy of CB307 were assessed in the CB307 monotherapy expansion cohort and in combination with pembrolizumab. Results: CB307 was administered to 75 patients. CB307 was given once every 7 days as monotherapy (N = 50) or in combination with pembrolizumab (N = 25). Two dose-limiting toxicities (grade 3 transient transaminitis) were observed. A total of three grade 3 transaminitis events (one in the monotherapy cohort and two in the combination cohort) were observed, and none involved bilirubin elevation. Durable RECIST responses were observed in two patients with metastatic castration-resistant prostate cancer enrolled in the 800 mg CB307 monotherapy and in one patient in the combination cohort (overall response rates: 11.1% and 7.1%, respectively). A disease control rate (DCR) of 50% was observed in patients enrolled in the 800 mg CB307 monotherapy cohort and 42.9% in the combination cohort. In a post hoc analysis, the response was numerically better in patients who had not received chemotherapy in the 6 months prior to starting CB307 (ORR = 20%, DCR = 60% vs. ORR = 0%, DCR = 37.5%). CB307 induces cytotoxic cell expansion in tumors and PD-L1 expression. Conclusions: CB307 was well tolerated as a monotherapy and in combination with pembrolizumab, and tumor responses were observed in patients with metastatic castration-resistant prostate cancer.

Background: The combination of trifluridine and tipiracil is indicated in patients with metastatic colorectal cancer previously treated or non-candidates to chemotherapy and biological therapies. This study in routine clinical practice aimed to describe the effectiveness and safety of trifluridine and tipiracil and identify prognostic factors in patients with metastatic colorectal cancer in Spain.Methods: This analysis was a retrospective, observational, multicenter study that included patients aged >_18 years who had received treatment with trifluridine/tipiracil for metastatic colorectal cancer in third-or subsequent lines.Results: Overall, 294 were evaluated. Trifluridine/tipiracilmedian (minimum, maximum) treatment duration was 3.5 (1.0-29.0) months, and 128 (43.5%) patients received subsequent treatments. One hundred (34%) patients showed disease control rate, and the median progression-free survival and overall survival from trifluridine/tipiracil treatment onset were 3.7 and 7.5 months, respectively. The most frequently reported adverse events were asthenia (all grades, 57.9%) and neutropenia (all grades, 51.3%). A 39.1% and 4.4% of the participants had a dose reduction and a treatment interruption due to toxicity. Patients with age >_65 years, low tumor burden, <= 2 metastasis sites, treatment dose reduction, neutropenia, and >_6 cycles, had significantly higher overall survival, progression-free survival, and response rate.Conclusions: This real-life study indicates that trifluridine/tipiracil shows effectiveness and safety in treating patients with metastatic colorectal cancer. The results show a profile of metastatic colorectal cancer patients with previously unknown prognostic factors who have a more significant benefit from treatment with trifluridine/tipiracil in routine clinical practice.