The interplay between drugs and microbiota is critical for successful treatment. An accumulating amount of evidence has identified the significant impact of intestinal microbiota composition on cancer treatment response, particularly immunotherapy. The possible molecular pathways of the interaction between immune checkpoint inhibitors (ICIs) and the microbiome can be used to reverse immunotherapy tolerance in cancer by using various kinds of interventions on the intestinal bacteria. This paper aimed to review the data available on how the antibiotic-related changes in human microbiota during colorectal cancer (CRC) treatment can affect and determine ICI treatment outcomes. We also covered the data that support the potential intimate mechanisms of both local and systemic immune responses induced by changes in the intestinal microbiota. However, further better-powered studies are needed to thoroughly assess the clinical significance of antibiotic-induced alteration of the gut microbiota and its impact on CRC treatment by direct observations of patients receiving antibiotic treatment.
In the last two decades, the vision of a unique carcinogenesis model for colorectal carcinoma (CRC) has completely changed. In addition to the adenoma to carcinoma transition, colorectal carcinogenesis can also occur via the serrated pathway. Small non-coding RNA, known as microRNAs (miRNAs), were also shown to be involved in progression towards malignancy. Furthermore, increased expression of certain miRNAs in premalignant sessile serrated lesions (SSLs) was found, emphasizing their role in the serrated pathway progression towards colon cancer. Since miRNAs function as post-transcriptional gene regulators, they have enormous potential to be used as useful biomarkers for CRC and screening in patients with SSLs particularly. In this review, we have summarized the most relevant information about the specific role of miRNAs and their relevant signaling pathways among different serrated lesions and polyps as well as in serrated adenocarcinoma. Additional focus is put on the correlation between gut immunity and miRNA expression in the serrated pathway, which remains unstudied.
1063 Background: Rintodestrant, a potent, oral selective estrogen receptor degrader, competitively binds and degrades the estrogen receptor (ER), thus blocking ER signaling in tumors resistant to other endocrine therapies (ET). Results from parts 1 and 2 dose-escalation/expansion indicate that once-daily (QD) rintodestrant has a favorable safety profile and antitumor activity in patients (pts) with heavily pretreated ER+/HER2– advanced breast cancer (ABC), including those with ESR1 variants (Aftimos et al. SABCS 2020 [PS12-04, PD8-07]). The optimal dose of rintodestrant was 800 mg. Here, we present part 3, combining rintodestrant with the CDK4/6 inhibitor palbociclib. Methods: This open-label study evaluated rintodestrant in pts with ER+/HER2– ABC after progression on ET (NCT03455270). Part 3 assessed rintodestrant 800 mg QD + palbociclib 125 mg QD for 21 days every 28 days. Key eligibility criteria included ≤1 line of chemotherapy and/or ≤1 line of ET in the advanced setting, with ≥6 months of ET in the advanced setting and/or ≥24 months in the adjuvant setting. Prior CDK4/6 inhibitor therapy was not allowed. Primary objectives included safety and efficacy. Secondary objectives included pharmacokinetics and antitumor activity (RECIST v1.1). Exploratory objectives included mutation profiling (cell-free DNA) at baseline and cycle 1 day 15. Results: Enrollment occurred Jul–Oct 2020. As of Dec 9, 2020, 40 pts were treated, with a median age of 58 years (35–76) and ECOG PS of 0 (70%) or 1 (30%); 20% had de novo stage 4 disease, 10% bone-only, and 68% visceral metastases. Median number of visceral sites was 1 (0–3): 30% of pts with lung and 40% with liver involvement. Median number of prior lines in the advanced setting was 1 (0–2), including chemotherapy (48%), fulvestrant (15%), and aromatase inhibitors (50%). Most recent ET was given in the adjuvant and metastatic settings in 28% and 73% of pts, respectively. Rintodestrant-related adverse events (AEs) were reported in 8% of pts—all nonserious and grade 2—and included nausea (3%), vomiting (3%), and neutropenia (3%). The most common (≥10%) treatment-related AEs (rintodestrant and/or palbociclib) were neutropenia (88%), leukopenia (45%), anemia (10%), and thrombocytopenia (10%); grade 3/4 neutropenia was 38%/15%, in line with the safety profile of palbociclib. No deaths or treatment discontinuations due to AEs were reported. At data cutoff (median treatment duration of 3 months [1.5–4.6]), 28 pts (70%) remained on study treatment, 2 (5%) had a confirmed partial response, and 27 (68%) had stable disease. Additional efficacy and pharmacodynamic data will be presented. Conclusions: Rintodestrant, as monotherapy or combined with palbociclib, continues to demonstrate an excellent safety/tolerability profile with promising antitumor activity in pts with ER+/HER2– ABC, including those with ESR1 variants. Clinical trial information: NCT03455270 .
BackgroundImmune checkpoint inhibitors (ICIs) have made a paradigm shift in clinical oncology due to unprecedented long-term remissions. However, only a small proportion of patients respond to ICI therapy. It is, therefore, essential to understand the mechanisms driving therapy resistance and to develop strategies for increasing response rates. We previously demonstrated that in response to various cancer treatment modalities, the host activates a range of biological processes that promote tumor regrowth and metastasis. Here, we characterize the host-mediated response to ICI therapy, and investigate its contribution to therapy resistance.MethodsTumor cell migration, invasion and motility were assessed in the presence of plasma from ICI-treated mice and patients. Immune cell composition in peripheral blood and tumors of ICI-treated mice was assessed by flow and mass cytometry. Plasma host factors driving tumor aggressiveness were identified by proteomic profiling, followed by bioinformatic analysis. The therapeutic effect of inhibiting host-mediated processes in ICI-treated mice was assessed in a tumor model.ResultsTumor cells exhibit enhanced migratory and invasive properties in vitro on exposure to plasma from anti-PD1-treated mice. Moreover, mice intravenously injected with plasma-exposed tumor cells display increased metastatic burden and mortality rate in comparison to control arms. Furthermore, tumors from anti-PD1-treated mice as well as Matrigel plugs containing plasma from anti-PD1-treated mice are highly infiltrated with immune cell types associated with both antitumor and protumor activity. These collective findings suggest that anti-PD1 treatment induces a systemic host response that potentially counteracts the drug’s therapeutic activity. Proteomic profiling of plasma from anti-PD1-treated mice reveals an activation of multiple biological pathways associated with tumor aggressiveness. Consequently, blocking IL-6, one of the key drivers of the identified biological pathways, counteracts ICI-induced metastatic properties in vitro and improves ICI treatment efficacy in vivo. Lastly, plasma samples from ICI-treated non-small cell lung cancer patients differentially affect tumor cell aggressiveness in vitro, with enhanced tumor cell motility correlating with a worse clinical outcome.ConclusionsICI therapy induces host-mediated processes that contribute to therapy resistance. Identification and analysis of such processes may lead to the discovery of biomarkers for clinical response and strategies for overcoming therapy resistance.
Approved CDK4/6 inhibitors have demonstrated significant improvements in progression free survival when combined with fulvestrant in patients with HR+/HER2- advanced breast cancer, though limited by neutropenia and gastrointestinal side effects. Lerociclib is a potent selective CDK4/6 inhibitor with a differentiated PK/PD profile from currently approved CDK4/6 inhibitors that has demonstrated clinical proof-of-concept (Phase 1b data ASCO 2018). This Phase 1b/2a study assesses lerociclib dose escalation in combination with 500 mg fulvestrant using a 3+3 design followed by dose expansion in patients with metastatic or locally advanced HR+/HER2- breast cancer that had progressed following endocrine therapy. Up to two prior chemotherapies in Phase 1b and one prior in Phase 2a in the advanced setting are allowed. Prior fulvestrant was excluded for all patients; prior CDK4/6 inhibitors were excluded in Phase 2a only. Lerociclib is administered daily without a drug holiday. The objectives are to evaluate DLTs, safety, tolerability, PK, and tumor response and to determine the recommended dose and schedule (QD or BID) of lerociclib administered with fulvestrant for randomized trials. The BID dosing regimen demonstrated optimal safety, tolerability, and antitumor activity. To date, 35 patients (6 patients @ 100 mg BID, 9 patients @ 150 mg BID, 17 patients @ 200 mg BID, and 3 patients @ 250 mg BID) with mean age of 54 years, ECOG of 0 (86%) or 1 (14%), and a median of two prior anticancer therapies in the advanced setting have received lerociclib + fulvestrant for up to 804 days. A dose proportional increase in drug exposure has been observed. The most common lerociclib-related adverse events were neutropenia (63%), leukopenia (57%), nausea (37%), anemia (29%), diarrhea (20%), and thrombocytopenia (20%). The rates of lerociclib-related Grade 3 and Grade 4 neutropenia were 29% and 9%, respectively. Following an initial decline, ANC plateaued beginning at week 4. There were no reports of Grade 3 or greater nausea, vomiting, or diarrhea. One DLT of dose interruption due to Grade 2 fatigue and nausea was observed at 200 mg BID. There have been no reports of venous thromboembolism, QT prolongation or drug-induced liver injury. Twenty patients were evaluable for tumor response based on RECIST v1.1. Five patients (25%) had a confirmed PR; 8 patients (40 %) had stable disease; 6 patients (30 %) had PD. The CBR (CR + PR + SD ≥ 24 weeks) was 67% (12 of 18 patients either had SD at the week 24 tumor assessments or achieved an objective response). A population PK/PD/efficacy model was developed, and simulation data are concordant with existing clinical results. Additional patients are being enrolled at 150 mg BID and 200 mg BID, and updated data will be presented. Lerociclib, dosed BID with no drug holiday, has a favorable safety profile with low rates of gastrointestinal AEs and Grade 3/4 neutropenia, as well as encouraging antitumor activity in patients with HR+/HER2- advanced breast cancer. Phase 2b is ongoing to confirm the BID dose (150 mg or 200 mg) for randomized clinical trials. Clinical trial information: NCT02983071. Citation Format: Iurie Bulat, Marina Maglakelidze, Carmen Murias, Boris Krastev, Richard D Baird, Andrew M Wardley, Rebecca Roylance, Adrian Crijanovschi, Maia Gogiladze, Yili Pritchett, Amy McCullough, Chao Li, Jessica A Sorrentino, Rajesh Malik, Andrew P Beelen. Dose escalation and expansion study of lerociclib (G1T38), an oral CDK4/6 inhibitor, dosed with no drug holiday in combination with fulvestrant in patients with HR+/HER2- advanced breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P1-19-17.
Background: CDK4/6 inhibitors (CDK4/6i) combined with fulvestrant (F) are the established standard of care for HR+/HER2-advanced breast cancer (ABC). Two of the three approved CDK4/6i cause dose-limiting neutropenia requiring a drug holiday, and the third is limited by gastrointestinal (GI) toxicity. Lerociclib is a potent, selective CDK4/6i that is dosed continuously. Initial data presented at SABCS 2019 indicated that lerociclib + F had low rates of GI toxicity and Grade 4 neutropenia, and antitumor activity was comparable with other CDK4/6i + F combinations.Methods: This phase I/II study assessed lerociclib with 500 mg F in patients (pts) with HR+/HER2-ABC that had progressed following endocrine therapy. Up to 2 prior chemotherapies in the advanced setting in phase I (dose escalation), and 1 prior in phase II (dose expansion) were allowed. Prior F and CDK4/6i exposure were excluded in phase II. The objectives were to evaluate DLTs, safety, tolerability, PK, preliminary efficacy, and determine the recommended dose of lerociclib when combined with F for future randomized trials.Results: As of Jan 31, 2020, 110 pts had been enrolled across doses of 200e650 mg once daily and 100e250 mg twice daily (BID). Twenty pts received 150 mg BID for a median 6.9 (range 1.7e27.8) months, with median age of 55 years (range 33e84), ECOG of 0 (85%), and median 1 line (range 0e5) of prior anticancer therapy in the advanced setting. The most common lerociclib-related AEs at 150 mg BID were neutropenia (55%), leukopenia (40%), diarrhea (20%), and anemia (20%). Rates of Grade 3 and 4 neutropenia were 30% and 5%, respectively. There were no reports of Grade 3 nausea, vomiting, or diarrhea. Nineteen pts at 150 mg BID were evaluable for tumor response based on RECIST version 1.1. Six pts (32%) had a confirmed PR; 9 (47%) had SD; 4 (21%) had PD. The CBR (CR+PR+SD 24 weeks) was 74% (14/19).Subgroup analyses revealed that pts who received no prior chemotherapy in the advanced setting (9/19 pts) had the highest CBR of 89%.Conclusions: Lerociclib 150 mg BID dosed continuously demonstrated a differentiated profile with low rates of GI toxicity and Grade 3/4 neutropenia. Efficacy compares favorably to approved CDK4/6i + F combinations.Clinical trial identification: NCT02983071.
The genetic and metabolomic abundance of the microbiome exemplifies that the microbiome comprises a more extensive set of genes than the entire human genome, which justifies the numerous metabolic and immunological interactions between the gut microbiota, macroorganisms and immune processes. These interactions have local and systemic impacts that can influence the pathological process of carcinogenesis. The latter can be promoted, enhanced or inhibited by the interactions between the microbiota and the host. This review aimed to present evidence that interactions between the host and the gut microbiota might be a significant exogenic factor for cancer predisposition. It is beyond doubt that the cross-talk between microbiota and the host cells in terms of epigenetic modifications can regulate gene expression patterns and influence cell fate in both beneficial and adverse directions for the host’s health. Furthermore, bacterial metabolites could shift pro- and anti-tumor processes in one direction or another. However, the exact mechanisms behind these interactions are elusive and require large-scale omics studies to better understand and possibly discover new therapeutic approaches for cancer.
No abstract
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.