Search

BACKGROUND: The alkaloid camptothecin analog SN38 is a potent antineoplastic agent, but cannot be used directly for clinical application due to its poor water solubility. Currently, the prodrug approach on SN38 has resulted in 3 FDA-approved cancer therapeutics, irinotecan, ONIVYDE, and Trodelvy. However, only 2-8% of irinotecan can be transformed enzymatically in vivo into the active metabolite SN38, which severely limits the drugs efficacy. While numerous drug delivery systems have been attempted to achieve effective SN38 delivery, none have produced drug products with antitumor efficacy better than irinotecan in clinical trials. Therefore, novel approaches are urgently needed for effectively delivering SN38 to cancer cells with better efficacy and lower toxicity. METHODS: Based on the unique properties of human serum albumin (HSA), we have developed a novel single protein encapsulation (SPE) technology to formulate cancer therapeutics for improving their pharmacokinetics (PK) and antitumor efficacy and reducing their side effects. Previous application of SPE technology to doxorubicin (DOX) formulation has led to a promising drug candidate SPEDOX-6 (FDA IND #, 152154), which will undergo a human phase I clinical trial. Using the same SPE platform on SN38, we have now produced two SPESN38 complexes, SPESN38-5 and SPESN38-8. We conducted their pharmacological evaluations with respect to maximum tolerated dose, PK, and in vivo efficacy against colorectal cancer (CRC) and soft tissue sarcoma (STS) in mouse models. RESULTS: The lyophilized SPESN38 complexes can dissolve in aqueous media to form clear and stable solutions. Maximum tolerated dose (MTD) of SPESN38-5 is 250 mg/kg by oral route (PO) and 55 mg/kg by intravenous route (IV) in CD-1 mice. SPESN38-8 has the MTD of 45 mg/kg by IV in the same mouse model. PK of SPESN38-5 by PO at 250 mg/kg gave mouse plasma AUC0-∞ of 0.05 and 4.5 nmol × h/mL for SN38 and SN38 glucuronidate (SN38G), respectively, with a surprisingly high molar ratio of SN38G:SN38 = 90:1. However, PK of SPESN38-5 by IV at 55 mg/kg yielded much higher mouse plasma AUC0-∞ of 19 and 28 nmol × h/mL for SN38 and SN38G, producing a much lower molar ratio of SN38G:SN38 = 1.5:1. Antitumor efficacy of SPESN38-5 and irinotecan (control) was evaluated against HCT-116 CRC xenograft tumors. The data indicates that SPESN38-5 by IV at 55 mg/kg is more effective in suppressing HCT-116 tumor growth with lower systemic toxicity compared to irinotecan at 50 mg/kg. Additionally, SPESN38-8 and DOX (control) by IV were evaluated in the SK-LMS-1 STS mouse model. The results show that SPESN38-8 at 33 mg/kg is highly effective for inhibiting SK-LMS-1 tumor growth with low toxicity, in contrast to DOXs insensitivity to SK-LMS-1 with high toxicity. CONCLUSION: SPESN38 complexes provide a water soluble SN38 formulation. SPESN38-5 and SPESN38-8 demonstrate better PK values, lower toxicity, and superior antitumor efficacy in mouse models, compared with irinotecan and DOX.

Multilabel learning involving hundreds of thousands or even millions of labels is referred to as extreme multilabel learning (XML), in which the labels often follow a power-law distribution with the majority occurring in very few data points as tail labels. Recent years have witnessed the intensive use of deep-learning methods for high-performance XML, but they are typically optimized for the head labels with abundant training instances and less consider the performance on tail labels, which, however, like the needles in haystacks, are often the focus of attention in real-life applications. In light of this, we present BoostXML, a deep learning-based XML method for extreme multilabel text classification, enhanced greatly by gradient boosting. In BoostXML, we pay more attention to tail labels in each Boosting Step by optimizing the residual mostly from unfitted training instances with tail labels. A Corrective Step is further proposed to avoid the mismatching between the text encoder and weak learners during optimization, which reduces the risk of falling into local optima and improves model performance. A Pretraining Step is also introduced in the initial stage of BoostXML to avoid exorbitant bias to tail labels. Extensive experiments on five benchmark datasets with state-of-the-art baselines demonstrate the advantage of BoostXML in tail-label prediction.

DDX5 (p68) is a well-known multifunctional DEAD-box RNA helicase and a transcription cofactor. Since its initial discovery more than three decades ago, DDX5 is gradually recognized as a potential biomarker and target for the treatment of various cancer types. Studies over the years significantly expanded our understanding of the functional diversity of DDX5 in various cancer types and extended our knowledge of its Mechanism of Action (MOA). This provides a rationale for the development of novel cancer therapeutics by using DDX5 as a biomarker and a therapeutic target. However, while most of the published studies have found DDX5 to be an oncogenic target and a cancer treatment-resistant biomarker, a few studies have reported that in certain scenarios, DDX5 may act as a tumor suppressor. After careful review of all the available relevant studies in the literature, we found that the multiple functions of DDX5 make it both a superior independent oncogenic biomarker and target for targeted cancer therapy. In this article, we will summarize the relevant studies on DDX5 in literature with a careful analysis and discussion of any inconsistencies encountered, and then provide our conclusions with respect to understanding the MOA of FL118, a novel small molecule. We hope that such a review will stimulate further discussion on this topic and assist in developing better strategies to treat cancer by using DDX5 as both an oncogenic biomarker and therapeutic target., Competing Interests: FL118 and FL118 core structure-based analogs will be further developed in Canget BioTekpharma LLC (www.canget-biotek.com), a spinoff company from Roswell Park Comprehensive Cancer Center (www.roswellpark.org). FL and XL are two of the eighteen initial investors of Canget for development of FL118 and FL118 core structure platform-relevant anticancer agents., (AJCR Copyright © 2021.)

Mutation-activated Kras in cancer cells is a well-known challenging treatment-resistant factor that plays a critical role in treatment resistance. Human colorectal cancer (CRC) has four major Kras mutations; Kras G12D (34.2%), Kras G12V (21%), Kras G13D (20%) and Kras G12C (8.4%). Here, we report that while FL118 (a novel inhibitor of survivin, Mcl-1, XIAP, cIAP2 and MdmX) exhibits high efficacy to kill CRC cells and eliminate CRC tumors, CRC cells/tumors with different Kras mutation subtypes in the defined p53/APC genetic statuses exhibit different sensitivity to FL118 treatment. Using CRC cell lines, SW620 (Kras G12V , mutant p53, mutant APC), DLD-1 (Kras G13D , wild type p53, mutant APC) and SNU-C2B (Kras G12D , mutant p53, wild type APC), we demonstrated that silencing of Kras G12V and Kras G12D using Kras-specific shRNA significantly increased CRC cell IC 50 , while silencing of Kras G13D decreased the CRC cell IC 50 . This finding suggests that both Kras G12V and Kras G12D are required for showing higher FL118 efficacy, while the presence of Kras G13D could somehow decrease FL118 efficacy under the defined p53/APC genetic status. Consistent with this notion, silencing of Kras G12V in SW620 cells decreased FL118-induced apoptosis, while silencing of Kras G13D in DLD-1 cells increased the FL118-induced apoptosis. Furthermore, forced expression of Kras G12V in SW620 cells increased FL118-induced apoptosis, while forced expression of Kras G13D in DLD-1 cells decreased FL118-induced apoptosis. Additionally, FL118 induced differential reactive oxygen species (ROS) production in SW620, DLD-1 and SNU-C2B cells. Our in vivo studies in animal models further confirmed that SW620 tumors are the most sensitive tumor to FL118 treatment; SNU-C2B tumors are the second most sensitive tumor to FL118 treatment; and the DLD-1 tumors are the least sensitive tumor. These findings would be useful for predicting FL118 sensitivity to patients' CRC tumors with the defined Kras mutation subtypes under the defined p53/APC genetic status., Competing Interests: FL118 and FL118 core structure-based analogues will be further developed in Canget BioTekpharma LLC (www.canget-biotek.com), a Roswell Park Cancer Institute-spinoff company. FL, XL are initial investors of Canget for development of FL118 and FL118 core structure-relevant anticancer agents and own Canget equity., (AJTR Copyright © 2021.)

Purpose: The microenvironment of multiple myeloma (MM) can critically impair therapy outcome, including immunotherapies. In this context, we have earlier demonstrated that bone marrow mesenchymal stromal cells (BMMSC) protect MM cells against the lytic machinery of MM-reactive cytotoxic T cells (CTL) and daratumumab-redirected natural killer (NK) cells through the upregulation of antiapoptotic proteins Survivin and Mcl-1 in MM cells. Here, we investigated the significance of this mode of immune escape on T cells engineered to express chimeric antigen receptors (CAR T cells)., Experimental Design: We tested the cytolytic ability of a panel of 10 BCMA-, CD38-, and CD138-specific CAR T cells with different affinities against a model MM cell line and against patient-derived MM cells in the presence versus absence of BMMSCs., Results: Although BMMSCs hardly protected MM cells from lysis by high-affinity, strongly lytic BCMA- and CD38-CAR T cells, they significantly protected against lower affinity, moderately lytic BCMA-, CD38-, and CD138-specific CAR T cells in a cell-cell contact-dependent manner. Overall, there was a remarkable inverse correlation between the protective ability of BMMSCs and the lytic activity of all CAR T cells, which was dependent on CAR affinity and type of costimulation. Furthermore, BMMSC-mediated resistance against CAR T cells was effectively modulated by FL118, an inhibitor of antiapoptotic proteins Survivin, Mcl-1, and XIAP., Conclusions: These results extend our findings on the negative impact of the microenvironment against immunotherapies and suggest that outcome of CAR T cell or conventional CTL therapies could benefit from inhibition of antiapoptotic proteins upregulated in MM cells through BMMSC interactions., (©2021 American Association for Cancer Research.)