DT2216, a Synthetic Proteolytic Selectively Targeting Bcl-XL for Ubiquitination and Degradation in Tumor Cells but Not in Platelets, Is a Safer and More Potent Antitumor Agent Than Navitoclax

The evasion of apoptosis, or programmed cell death, is a hallmark of cancer, which promotes tumor initiation and progression. The evasion is in part attributable to the over-expression of anti-apoptotic proteins in the Bcl-2 family. In addition, chemotherapy and radiation can upregulate the expression of the Bcl-2 family in cancer cells, which renders them more resistance to cancer therapy. The most common Bcl-2 family member over-expressed in many solid tumor cells and a fraction of leukemia and lymphoma cells is Bcl-XL and its expression is also highly correlated with resistance to cancer therapy independent of p53 status in many cancers. Therefore, Bcl-XL is one of the most important validated cancer cell targets.Inhibition of Bcl-XL with a small molecule inhibitor has been extensively exploited as a molecularly targeted therapeutic strategy against cancer, resulting in the discovery of several Bcl-2/XL and Bcl-XL inhibitors as promising anti-cancer drug candidates including navitoclax. Unfortunately, these inhibitors failed to become anticancer drugs because platelets are also dependent on Bcl-XL for survival. Therefore, inhibition of Bcl-XL with Bcl-2/XL and Bcl-XL inhibitors causes severe reduction in platelets or thrombocytopenia, an on-target and dose-limiting toxicity, which prevents their use as an effective anticancer drug in clinic. To overcome this problem, we generated a series of novel bifunctional molecules that targeting Bcl-XL to the ubiquitin-proteasome sys...
Source: Blood - Category: Hematology Authors: Tags: 614. Acute Lymphoblastic Leukemia: Therapy, excluding Transplantation: Poster II Source Type: research

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Irreversible T cell exhaustion limits the efficacy of programmed cell death 1 (PD-1) blockade. We observed that dual CD40-TLR4 stimulation within a single tumor restored PD-1 sensitivity and that this regimen triggered a systemic tumor-specific CD8+ T cell response. This approach effectively treated established tumors in diverse syngeneic cancer models, and the systemic effect was dependent on the injected tumor, indicating that treated tumors were converted into necessary components of this therapy. Strikingly, this approach was associated with the absence of exhausted PD-1hi T cells in treated and distant tumors, while s...
Source: Journal of Clinical Investigation - Category: Biomedical Science Authors: Source Type: research
Although modifications of gut microbiota with antibiotics (Abx) influence mouse skin and cardiac allografts, its role in orthotopic liver transplantation (OLT) remains unknown. We aimed to determine whether and how recipient Abx pretreatment may affect hepatic ischemia-reperfusion injury (IRI) and OLT outcomes. Mice (C57BL/6) with or without Abx treatment (10 days) were transplanted with allogeneic (BALB/c) cold-stored (18 hours) livers, followed by liver and blood sampling (6 hours). We divided 264 human OLT recipients on the basis of duration of pre-OLT Abx treatment into control (Abx-free/Abx
Source: Journal of Clinical Investigation - Category: Biomedical Science Authors: Source Type: research
Organ transplantation is now a preferred treatment for end-stage organ failure. Among the challenges for ensuring excellent clinical outcomes for transplant recipients is good initial allograft function at the time of organ implantation. This is determined in part by the functional status of the donor and donor organ, functional status of the recipient, and conduct of the operative procedure. Despite optimization of these variables, organ transplantation is still often plagued by substantial initial dysfunction, variably referred to as slow or delayed graft function, or in the most extreme cases, primary graft nonfunction ...
Source: Journal of Clinical Investigation - Category: Biomedical Science Authors: Source Type: research
Active surveillance (AS) has been widely accepted as a first-line management approach in men with low-risk prostate cancer. While AS provides an avenue to reduce risk of overtreatment without compromising oncological safety, there remains a lack of consensus on the optimal approach to monitoring. An ideal surveillance strategy would be one that minimizes invasive testing such as prostate biopsy without conceding adverse oncologic outcomes. Thus, several studies have sought to identify men at higher risk of reclassification so as to more carefully select when biopsy is truly necessary.
Source: Urology - Category: Urology & Nephrology Authors: Source Type: research
In “National trends in the utilization of androgen deprivation therapy for very low risk prostate cancer,” the authors demonstrate a significant decline in the use of primary androgen deprivation (pADT), for very low risk prostate cancer. By 2015, only 1.7% of men in this population received pADT, representing a furthering of trends witnessed in the early 21st century, and which have been previously described.1,2
Source: Urology - Category: Urology & Nephrology Authors: Source Type: research
ConclusionReal-time indocyanine green fluorescence imaging may be particularly helpful for delineating the anatomical surgical plane and determining the appropriate division point of the hepatic duct during laparoscopic living donor hepatectomy.
Source: Journal of Gastrointestinal Surgery - Category: Surgery Source Type: research
ConclusionThe novel approach for transthoracic hepatectomy was safe and feasible for lesions of segment VIII in selected patients with cirrhosis,8 which was associated with reduced blood loss and a safe surgical margin.
Source: Journal of Gastrointestinal Surgery - Category: Surgery Source Type: research
Hi everyone I failed a course by a single question (0.2%) and as a result I have to take a Remediation Exam. The exam is on our Fundamentals Course which is all of the basics sciences. It is 2 days away and I am starting to panic. It is on all of Immuno, all of BioChem, all Anatomy, all Micro, Anti-biotics, Anti-cancers, Anti-fungals, Fundamentals of Pathology, Infectious Disease and pretty much anything you can think of. I have been studying for a month but I feel like I just cant... Remediation Exam
Source: Student Doctor Network - Category: Universities & Medical Training Authors: Tags: Medical Students - MD Source Type: forums
This study investigates the role of LAMC2 in epithelial-mesenchymal transition (EMT) and angiogenesis in CCA and explores the underlying mechanism(s) . Differentially expressed genes related to CCA were initially screened using a microarray analysis, and the interaction between LAMC2 and the EGFR signaling pathway was identified.
Source: American Journal of Pathology - Category: Pathology Authors: Tags: Regular article Source Type: research
Conclusions This review describes how leukocyte-heparanase can be a double-edged sword in tumor progression; it can enhance tumor immune surveillance and tumor cell clearance, but also promote tumor survival and growth. We also discuss the potential of using heparanase in leukocyte therapies against tumors, and the effects of heparanase inhibitors on tumor progression and immunity. We are just beginning to understand the influence of heparanase on a pro/anti-tumor immune response, and there are still many questions to answer. How do the pro/anti-tumorigenic effects of heparanase differ across different cancer types? Does...
Source: Frontiers in Oncology - Category: Cancer & Oncology Source Type: research
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