Tumor Reduction in Multiple Myeloma: New Concepts for New Therapeutics

The development of new resources for a more accurate diagnosis and response assessment in multiple myeloma has been a long process for decades, mainly since the middle of the 20th century. During this time, the succession of technical advances has run parallel to the better knowledge of disease biology and the availability of novel therapeutic strategies. The cornerstone of standardized criteria to uniformly evaluate the disease response in myeloma dates back to the 1990s when the key role of complete remission was established. Since then, different updates have been implemented according to available scientific evidences not always without certain controversies. The progressive improvements in survival results of myeloma patients and the growing quality of responses due to the novel therapies have led to the need of developing new tools for better monitoring of tumor burden. In this way, the concept of minimal residual disease and its key value based on the prognostic significance and the clinical relevance has been consolidated during the last years, overcoming the value of conventional response criteria or classical adverse prognosis markers. Nevertheless, its precise role in the clinical management of myeloma patients to detect early treatment failure and trigger early rescue strategies is still pending to be defined. In this review, we revisit the major milestones in the understanding of tumor reduction in multiple myeloma until the most recent imaging techniques or liquid biopsy approaches, including a critical view of conventional response criteria, whose backbone has remained unchanged during the last 20 years.

Liver Transplantation for Hepatocellular Carcinoma: How Should We Improve the Thresholds?

Hepatocellular carcinoma (HCC) is the third highest cause of cancer-related mortality, and liver transplantation is the ideal treatment for this disease. The Milan criteria provided the opportunity for HCC patients to undergo LT with favorable outcomes and have been the international gold standard and benchmark. With the accumulation of data, however, the Milan criteria are not regarded as too restrictive. After the implementation of the Milan criteria, many extended criteria have been proposed, which increases the limitations regarding the morphological tumor burden, and incorporates the tumor’s biological behavior using surrogate markers. The paradigm for the patient selection for LT appears to be shifting from morphologic criteria to a combination of biologic, histologic, and morphologic criteria, and to the establishment of a model for predicting post-transplant recurrence and outcomes. This review article aims to characterize the various patient selection criteria for LT, with reference to several surrogate markers for the biological behavior of HCC (e.g., AFP, PIVKA-II, NLR, 18F-FDG PET/CT, liquid biopsy), and the response to locoregional therapy. Furthermore, the allocation rules in each country and the present evidence on the role of down-staging large tumors are addressed.

Targeted Delivery of Exosomes Armed with Anti-Cancer Therapeutics

Among extracellular vesicles, exosomes have gained great attention for their role as therapeutic vehicles for delivering various active pharmaceutical ingredients (APIs). Exosomes “armed” with anti-cancer therapeutics possess great potential for an efficient intracellular delivery of anti-cancer APIs and enhanced targetability to tumor cells. Various technologies are being developed to efficiently incorporate anti-cancer APIs such as genetic materials (miRNA, siRNA, mRNA), chemotherapeutics, and proteins into exosomes and to induce targeted delivery to tumor burden by exosomal surface modification. Exosomes can incorporate the desired therapeutic molecules via direct exogenous methods (e.g., electroporation and sonication) or indirect methods by modifying cells to produce “armed” exosomes. The targeted delivery of “armed” exosomes to tumor burden could be accomplished either by “passive” targeting using the natural tropism of exosomes or by “active” targeting via the surface engineering of exosomal membranes. Although anti-cancer exosome therapeutics demonstrated promising results in preclinical studies, success in clinical trials requires thorough validation in terms of chemistry, manufacturing, and control techniques. While exosomes possess multiple advantages over synthetic nanoparticles, challenges remain in increasing the loading efficiency of anti-cancer agents into exosomes, as well as establishing quantitative and qualitative analytical methods for monitoring the delivery of in vivo administered exosomes and exosome-incorporated anti-cancer agents to the tumor parenchyma.

Emodin reduces tumor burden by diminishing M2-like macrophages in colorectal cancer

Emodin, a natural anthraquinone, has been shown to have anti-tumorigenic properties and may be an effective therapy for colorectal cancer (CRC). However, its clinical development has been hampered by a poor understanding of its mechanism of action. The purpose of this study was to 1) evaluate the efficacy of emodin in mouse models of intestinal/colorectal cancer and 2) to examine the impact of emodin on macrophage behavior in the context of CRC. We utilized a genetic model of intestinal cancer (ApcMin/+) and a chemically induced model of CRC (AOM/DSS). Emodin was administered orally (40 mg/kg or 80 mg/kg in AOM/DSS and 80mg/kg in ApcMin/+) 3x/week to observe its preventative effects. Emodin reduced polyp count and size in both rodent models (p<0.05). We further analyzed the colon microenvironment of AOM/DSS mice and found that mice treated with emodin exhibited lower pro-tumorigenic M2-like macrophages and a reduced ratio of M2/M1 macrophages within the colon (p<0.05). Despite this, we did not detect any significant changes in M2-associated cytokines (IL10, IL4, and Tgfb1) nor M1-associated cytokines (IL6, TNFα, IL1β, and IFNγ) within excised polyps. However, there was a significant increase in NOS2 expression (M1 marker) in mice treated with 80 mg/kg emodin (p<0.05). To confirm emodin's effects on macrophages, we exposed bone marrow-derived macrophages (BMDMs) to C26 colon cancer cell conditioned media. Supporting our in vivo data, emodin reduced M2-like macrophages. Overall, these data support the development of emodin as a natural compound for prevention of CRC given its ability to target pro-tumor macrophages.

Reciprocal epigenetic Sox2 regulation by SMAD1-SMAD3 is critical for anoikis resistance and metastasis in cancer

Growth factors in the tumor environment are key regulators of cell survival and anoikis resistance during metastasis. Here we reveal significant dichotomy between TGF-β superfamily growth factors BMP and TGF-β/activin and their downstream SMAD effectors in regulation of anchorage-independent tumor cell survival in ovarian cancer. Gene expression profiling uncovered the transcription factor Sox2 as a key signaling node regulated in an opposing manner by anoikis-promoting BMP2 4 and 9 and anoikis-suppressing TGF-β and activin A. Mechanistically, repression of Sox2 by BMPs is mediated by type I receptors ALK2 and ALK3 induced SMAD1 activation, leading to SMAD1-dependent histone H3K27me3 recruitment and DNA methylation at SOX2s promoter. Conversely, TGF-β and activin A promote Sox2 expression directly by ALK5-mediated SMAD3 activation and histone H3K4me3 recruitment. Increased Sox2 expression promotes anoikis resistance, while decreasing Sox2 levels conversely reduces anoikis resistance and activates cell death pathways. Additionally, administrating BMP9 as a strategy to reduce Sox2 robustly inhibits intraperitoneal tumor burden and increases survival in multiple ovarian cancer xenograft models. Importantly, BMP-driven SMAD1 signaling can override the effects of TGF-β and activin on Sox2 regulation, which has potential clinical significance as we find high TGF-β levels in patient ascites. Our findings highlight the contrasting regulation of anoikis by distinct SMAD signaling pathways that are dependent on a novel dichotomous regulation of Sox2 and implicate the use of a subset of BMPs as a therapeutic strategy in cancer

Prognostic Factor Analysis and Nomogram Construction of Primary Retroperitoneal Liposarcoma: A Review of 10 Years of Treatment Experience in a Single Asian Cohort of 211 Cases

ObjectiveThis study intended to retrospectively analyze the data of patients with primary retroperitoneal liposarcoma in a single Asian large-volume sarcoma center and to establish nomograms focused on PRLPS for predicting progression-free survival (PFS) and overall survival (OS).MethodsA total of 211 patients treated surgically for primary, non-metastatic retroperitoneal liposarcoma during 2009–2021 were identified, and clinicopathologic variables were analyzed. PFS and OS nomograms were built based on variables selected by multivariable analysis. The discriminative and predictive ability of the nomogram was assessed by concordance index and calibration curve.ResultsThe median follow-up time was 25 months. A total of 117 (56%) were well-differentiated, 78 (37%) were dedifferentiated, 13 (6%) were myxoid, and 3 (1%) were pleomorphic morphology. Compared to the western population cohort reported by the Memorial Sloan-Kettering Cancer Center, the median age of patients in this cohort was younger (57 vs. 63 years), the tumor burden was lower (20 vs. 26 cm), and the proportion of patients with R0 or R1 resection was higher (97% vs. 81%). The 5-year PFS rate was 49%, and factors independently associated with PFS were symptoms at visit, preoperative needle biopsy, histologic subtypes, and postoperative hospital stay. The 5-year OS rate was 72%. American Society of Anesthesiologists Physical Status and Clavien-Dindo classification were independently associated with OS. The concordance indexes for PFS and OS nomograms were 0.702 and 0.757, respectively. The calibration plots were excellent.ConclusionsThe proposed nomogram provided a favorable reference for the treatment of primary retroperitoneal liposarcoma patients.

Systemic Delivery of mLIGHT-Armed Myxoma Virus Is Therapeutic for Later-Stage Syngeneic Murine Lung Metastatic Osteosarcoma

Cancers that metastasize to the lungs represent a major challenge in both basic and clinical cancer research. Oncolytic viruses are newly emerging options but successful delivery and choice of appropriate therapeutic armings are two critical issues. Using an immunocompetent murine K7M2-luc lung metastases model, the efficacy of MYXV armed with murine LIGHT (TNFSF14/CD258) expressed under virus-specific early/late promoter was tested in an advanced later-stage disease K7M2-luc model. Results in this model show that mLIGHT-armed MYXV, delivered systemically using ex vivo pre-loaded PBMCs as carrier cells, reduced tumor burden and increased median survival time. In vitro, when comparing direct infection of K7M2-luc cancer cells with free MYXV vs. PBMC-loaded virus, vMyx-mLIGHT/PBMCs also demonstrated greater cytotoxic capacity against the K7M2 cancer cell targets. In vivo, systemically delivered vMyx-mLIGHT/PBMCs increased viral reporter transgene expression levels both in the periphery and in lung tumors compared to unarmed MYXV, in a tumor- and transgene-dependent fashion. We conclude that vMyx-mLIGHT, especially when delivered using PBMC carrier cells, represents a new potential therapeutic strategy for solid cancers that metastasize to the lung.

NCoR1 and SMRT Fine-Tune Inflammatory Versus Tolerogenic Balance in Dendritic Cells By Differentially Regulating STAT3 Signaling

Dendritic cell (DC) fine-tunes inflammatory versus tolerogenic responses to protect from immune-pathology. However, the role of co-regulators in maintaining this balance is unexplored. NCoR1-mediated repression of DC immune-tolerance has been recently reported. Here we found that depletion of NCoR1 paralog SMRT (NCoR2) enhanced cDC1 activation and expression of IL-6, IL-12 and IL-23 while concomitantly decreasing IL-10 expression/secretion. Consequently, co-cultured CD4+ and CD8+ T-cells depicted enhanced Th1/Th17 frequency and cytotoxicity, respectively. Comparative genomic and transcriptomic analysis demonstrated differential regulation of IL-10 by SMRT and NCoR1. SMRT depletion represses mTOR-STAT3-IL10 signaling in cDC1 by down-regulating NR4A1. Besides, Nfkbia and Socs3 were down-regulated in Ncor2 (Smrt) knockdown cDC1, supporting increased production of inflammatory cytokines. Moreover, studies in mice showed, adoptive transfer of SMRT knockdown cDC1 in OVA-DTH induced footpad inflammation led to increased Th1/Th17 and reduced tumor burden after B16 melanoma injection by enhancing oncolytic CD8+ T-cell frequency, respectively. We also depicted decreased Ncor2 expression in Rheumatoid Arthritis, a Th1/Th17 disease.

Preliminary Clinical Validation of a Filtration-Based CTC Assay for Tumor Burden and HER2 Status Monitoring in Metastatic Breast Cancer

<b><i>Background:</i></b> Bearing multidimensional tumor-relevant information ranging from genomic alterations to proteomic makeup, circulating tumor cells (CTCs) constitute a promising material for liquid biopsy. The clinical validity of CTCs has been most extensively studied in metastatic breast cancer (MBC). The Cellsearch assay is currently the most widely used, while alternative strategies are pursued. A filtration-based microfluidic device has been described for CTC enrichment, but its clinical relevance remains unknown. <b><i>Methods:</i></b> In this preliminary study, we prospectively enrolled 47 MBC patients and evaluated the performance of the abovementioned CTC assay for tumor burden monitoring and human epidermal growth factor receptor 2 (HER2) status determination. <b><i>Results:</i></b> At baseline, 51.1% patients (24/47) were CTC positive. CTC count and positivity were also significantly higher in samples that accompanied poorer radiographic response evaluations. Serial blood draws suggested that CTC count enabled more accurate monitoring of tumor burden than serum markers carcinoembryonic antigen and cancer antigen 15-3. Also, in contrast to previous reports, CTC-HER2 status was moderately consistent with tumor-HER2 status. CTC-HER2 status assessment was further supported by <i>HER2</i> copy number measurements in select samples. <b><i>Conclusion:</i></b> The preliminary results from this study suggest promise for the interrogated CDC assay in several aspects, including sensitive CTC detection, accurate disease status reflection, and HER2 status determination. More studies are warranted to validate these findings and further characterize the value of CTC assay.