Genetically Reprogrammed Exosomes for Immunotherapy of Acute Myeloid Leukemia.

Current treatments for acute myeloid leukemia (AML) remain challenging, characterized by poor clinical outcomes. Exosomes, cell-derived membranous vesicles, has been emerging as a new modality of therapy. Here we designed and generated genetically reprogrammed exosomes with surface displayed antibodies and immunoregulatory proteins, namely programmed immune-engaging exosomes (PRIME Exos).

Gene signatures derived from transcriptomic-causal networks stratify colorectal cancer patients for effective targeted therapy.

Background: Gene signatures derived from transcriptomic-causal networks offer potential for tailoring clinical care in cancer treatment by identifying predictive and prognostic biomarkers. This study aimed to uncover such signatures in metastatic colorectal cancer (CRC) patients to aid treatment decisions.

Methods: We constructed transcriptomic-causal networks and integrated gene interconnectivity into overall survival (OS) analysis to control for confounding genes.

Comprehensive characterization of MCL-1 in patients with colorectal cancer: Expression, molecular profiles, and outcomes.

Myeloid cell leukemia 1 (MCL-1) is a member of the B-cell lymphoma 2 protein family and has anti-apoptotic functions. Deregulation of MCL-1 has been reported in several cancers, including lung and breast cancer. In the present study, the association of MCL-1 expression with molecular features in colorectal cancer (CRC) has been highlighted.

A Phase 1b study of the OxPhos inhibitor ME-344 with bevacizumab in refractory metastatic colorectal cancer.

Antiangiogenic drugs may cause vascular normalization and correct hypoxia in tumors, shifting cells to mitochondrial respiration as the primary source of energy. In turn, the addition of an inhibitor of mitochondrial respiration to antiangiogenic therapy holds potential to induce synthetic lethality. This study evaluated the mitochondrial inhibitor ME-344 in combination with bevacizumab in patients with refractory metastatic colorectal cancer (mCRC).

A Phase 2 study of Savolitinib in Patients with MET Amplified Metastatic Colorectal Cancer.

Purpose: MET amplification (amp) is a driver of acquired resistance to epidermal growth factor receptor (EGFR) antibodies in patients with RAS wild-type (WT) metastatic colorectal cancer (mCRC). Savolitinib is an oral small molecule tyrosine kinase inhibitor that has demonstrated anti-tumor activity in MET-driven advanced solid tumors. We report the results of a phase 2 study of savolitinib in patients with mCRC with MET amp detected by circulating cell free (cf)DNA.

A phase I dose-escalation study of LRP5/6 antagonist BI 905677 in patients with advanced solid tumors.

Background: Aberrant Wnt pathway signaling has been implicated in the development of many cancers. Targeting of low-density lipoprotein receptor-related protein 5/6 (LRP5/6) co-receptors inhibits Wnt signaling and may be a novel therapy. BI 905677 is an LRP5/6 antagonist that has demonstrated preclinical antitumor activity.

Integrative multi-omics profiling of colorectal cancer from a Hispanic/Latino cohort of patients.

Colorectal cancer contributes to cancer-related deaths and health disparities in the Hispanic and Latino community. To probe both the biological and genetic bases of the disparities, we characterized features of colorectal cancer in terms of somatic alterations and genetic similarity. Specifically, we conducted a comprehensive genome-scale analysis of 67 Hispanic and Latino samples.

Nivolumab plus Ipilimumab in Microsatellite-Instability-High Metastatic Colorectal Cancer.

Background: Patients with microsatellite-instability-high (MSI-H) or mismatch-repair-deficient (dMMR) metastatic colorectal cancer have poor outcomes with standard chemotherapy with or without targeted therapies. Nivolumab plus ipilimumab has shown clinical benefit in nonrandomized studies of MSI-H or dMMR metastatic colorectal cancer.

Methods: In this phase 3 open-label trial, we randomly assigned patients with unresectable or metastatic colorectal cancer and MSI-H or dMMR status according to local testing to receive, in a 2:2:1 ratio, nivolumab plus ipilimumab, nivolumab alone, or chemotherapy with or without targeted therapies.

Trilaciclib prior to FOLFOXIRI/bevacizumab for patients with untreated metastatic colorectal cancer: phase 3 PRESERVE 1 trial.

Background: In metastatic colorectal cancer (mCRC), improvements in survival from combining leucovorin/fluorouracil/oxaliplatin/irinotecan (FOLFOXIRI) with bevacizumab have come at the risk of increased rates of high-grade toxicities. Trilaciclib is indicated to decrease the incidence of chemotherapy-induced myelosuppression in patients receiving standard-of-care chemotherapy for extensive-stage small cell lung cancer.

Methods: Patients with untreated mCRC were randomly assigned 1:1 to trilaciclib (n = 164) or placebo (n = 162) prior to FOLFOXIRI/bevacizumab for up to 12 cycles (induction), followed by trilaciclib or placebo prior to fluorouracil/leucovorin/bevacizumab (maintenance).

Clinical Applications of Circulating Tumor DNA Profiling in GI Cancers.

Over the next few years, the analysis of circulating tumor DNA (ctDNA) through liquid biopsy is expected to enter clinical practice and revolutionize the approach to biomarker testing and treatment selection in GI cancers. In fact, growing evidence support the use of ctDNA testing as a noninvasive, effective, and highly specific tool for molecular profiling in GI cancers. Analysis of blood ctDNA has been investigated in multiple settings including early tumor detection, minimal residual disease evaluation, tumor diagnosis and evaluation of prognostic/predictive biomarkers for targeted treatment selection, longitudinal monitoring of treatment response, and identification of resistance mechanisms.

Role of gene expression in colorectal cancer: a comprehensive molecular profiling study.

Background: In patients with colorectal cancer (CRC), the therapeutic effects of conventional immune checkpoint inhibitors targeting the adaptive immune system are largely limited to those with microsatellite instability-high tumors. Meanwhile, new immunotherapies targeting the innate immune system are attracting increasing attention. CD47 is a representative innate immune checkpoint involved in the evasion of tumor cell phagocytosis by macrophages.

Onvansertib in Combination With Chemotherapy and Bevacizumab in Second-Line Treatment of -Mutant Metastatic Colorectal Cancer: A Single-Arm, Phase II Trial.

Purpose: This phase II study evaluated the efficacy and tolerability of onvansertib, a polo-like kinase 1 (PLK1) inhibitor, in combination with fluorouracil, leucovorin, and irinotecan (FOLFIRI) + bevacizumab for the second-line treatment of -mutant metastatic colorectal cancer (mCRC).

Patients And Methods: This multicenter, open-label, single-arm study enrolled patients with -mutated mCRC previously treated with oxaliplatin and fluorouracil with or without bevacizumab. Patients received onvansertib (15 mg/m once daily on days 1-5 and 15-19 of a 28-day cycle) and FOLFIRI + bevacizumab (days 1 and 15).

Large-scale analysis of CDH1 mutations defines a distinctive molecular subset with treatment implications in gastric cancer.

Although histological and molecular classifications have been extensively studied for gastric cancer (GC), targeted therapies for GC remain limited. CDH1 mutations (MT) are characteristic of genomically stable GC and are associated with poor prognosis, but lack effective or targeted therapies. Here, we showed the overall mutation frequency of CDH1 was 9.

Phase I-II study of OBI-888, a humanized monoclonal IgG1 antibody against the tumor-associated carbohydrate antigen Globo H, in patients with advanced solid tumors.

Purpose: OBI-888 is a humanized, monoclonal IgG1 antibody specific to the tumor-associated carbohydrate antigen Globo H. We conducted a phase I-II study of OBI-888 in patients with advanced cancer.

Methods: Patients were treated with OBI-888 5, 10, or 20 mg/kg IV weekly in Part A ("3 + 3" design) and 20 mg/kg IV weekly in Part B (Simon's 2-stage design) (1 cycle = 28 days).

Consensus molecular subtyping of metastatic colorectal cancer expands biomarker-directed therapeutic benefit for patients with CMS1 and CMS2 tumors.

Background: We developed a whole transcriptome sequencing (WTS)-based Consensus Molecular Subtypes (CMS) classifier using FFPE tissue and investigated its prognostic and predictive utility in a large clinico-genomic database of CRC patients (n = 24,939).

Methods: The classifier was trained against the original CMS datasets using an SVM model and validated in an independent blinded TCGA dataset (88.0% accuracy).

Plant-based diet and survival among patients with metastatic colorectal cancer.

Background: A plant-based diet is associated with better survival among patients with nonmetastatic colorectal cancer (CRC), but its association in metastatic CRC is unknown.

Methods: Using an National Cancer Institute-sponsored trial (CALGB/SWOG 80405), we included 1284 patients who completed validated food frequency questionnaires at the initiation of metastatic CRC treatment. We calculated 3 indices: overall plant-based diet index (PDI), which emphasized consumption of all plant foods while reducing animal food intake; healthful plant-based diet index (hPDI), which emphasized consumption of healthful plant foods such as whole grains, fruits, and vegetables; and unhealthful plant-based diet index (uPDI), which emphasized consumption of less healthful plant foods such as fruit juices, refined grains, and sugar-sweetened beverages.

Mesothelin expression correlates with elevated inhibitory immune activity in patients with colorectal cancer.

The expression of the protein Mesothelin (MSLN) is highly variable in several malignancies, including colorectal cancer (CRC), and high levels are associated with aggressive clinicopathological features and worse patient survival. Colorectal cancer is both a common and deadly cancer; being the third most common in incidence and second most common cause of cancer-related death. While systemic therapy remains the primary therapeutic option for most patients with stage IV (metastatic; m) CRC, their disease eventually becomes treatment refractory, and 85% succumb within 5 years.

Understanding patient-derived tumor organoid growth through an integrated imaging and mathematical modeling framework.

Patient-derived tumor organoids (PDTOs) are novel cellular models that maintain the genetic, phenotypic and structural features of patient tumor tissue and are useful for studying tumorigenesis and drug response. When integrated with advanced 3D imaging and analysis techniques, PDTOs can be used to establish physiologically relevant high-throughput and high-content drug screening platforms that support the development of patient-specific treatment strategies. However, in order to effectively leverage high-throughput PDTO observations for clinical predictions, it is critical to establish a quantitative understanding of the basic properties and variability of organoid growth dynamics.

Genomic, immunologic, and prognostic associations of TROP2 (TACSTD2) expression in solid tumors.

Background: TROP2 (TACSTD2) expression is associated with decreased overall survival (OS) in some solid tumors, and the TROP2-targeting antibody-drug conjugate (ADC) sacituzumab govitecan has been approved in breast and urothelial carcinomas. We aimed to explore the multi-omic landscape associated with TACSTD2 gene expression in various solid tumors to identify patients most likely to benefit from this approach.

Methods: Breast (N = 11 246), colorectal (N = 15 425), hepatocellular (N = 433), pancreatic (N = 5488), and urothelial (N = 4125) tumors were stratified into quartiles by TACSTD2 gene expression, analyzed by next-generation DNA sequencing, whole transcriptome sequencing, and immunohistochemistry at Caris Life Sciences (Phoenix, AZ).

Botensilimab plus balstilimab in relapsed/refractory microsatellite stable metastatic colorectal cancer: a phase 1 trial.

Microsatellite stable metastatic colorectal cancer (MSS mCRC; mismatch repair proficient) has previously responded poorly to immune checkpoint blockade. Botensilimab (BOT) is an Fc-enhanced multifunctional anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) antibody designed to expand therapy to cold/poorly immunogenic solid tumors, such as MSS mCRC. BOT with or without balstilimab (BAL; anti-PD-1 antibody) is being evaluated in an ongoing expanded phase 1 study.