Selective and Potent PROTAC Degraders of c-Src Kinase.

Using dasatinib linked to E3 ligase ligands, we identified a potent and selective dual Csk/c-Src PROTAC degrader. We then replaced dasatinib, the c-Src-directed ligand, with a conformation-selective analogue that stabilizes the αC-helix-out conformation of c-Src. Using the αC-helix-out ligand, we identified a PROTAC that is potent and selective for c-Src.

Inhibitor of the Nuclear Transport Protein XPO1 Enhances the Anticancer Efficacy of KRAS G12C Inhibitors in Preclinical Models of KRAS G12C-Mutant Cancers.

Unlabelled: The identification of molecules that can bind covalently to KRAS G12C and lock it in an inactive GDP-bound conformation has opened the door to targeting KRAS G12C selectively. These agents have shown promise in preclinical tumor models and clinical trials. FDA has recently granted approval to sotorasib for KRAS G12C mutated non-small cell lung cancer (NSCLC).

Connecting the Human Microbiome and Pancreatic Cancer.

Pancreatic cancer is a deadly disease that is increasing in incidence throughout the world. There are no clear causal factors associated with the incidence of pancreatic cancer; however, some correlation to smoking, diabetes and alcohol has been described. Recently, a few studies have linked the human microbiome (oral and gastrointestinal tract) to pancreatic cancer development.

Nuclear Export Inhibitor KPT-8602 Synergizes with PARP Inhibitors in Escalating Apoptosis in Castration Resistant Cancer Cells.

Aberrant nuclear protein transport, often observed in cancer, causes mislocalization-dependent inactivation of critical cellular proteins. Earlier we showed that overexpression of exportin 1 is linked to higher grade and Gleason score in metastatic castration resistant prostate cancer (mCRPC). We also showed that a selective inhibitor of nuclear export (SINE) selinexor and second generation eltanexor (KPT-8602) could suppress mCRPC growth, reduce androgen receptor (AR), and re-sensitize to androgen deprivation therapy.

Gastric cancer: a comprehensive review of current and future treatment strategies.

Gastric cancer remains a major unmet clinical problem with over 1 million new cases worldwide. It is the fourth most commonly occurring cancer in men and the seventh most commonly occurring cancer in women. A major fraction of gastric cancer has been linked to variety of pathogenic infections including but not limited to Helicobacter pylori (H.

Gastric Cancer Heterogeneity and Clinical Outcomes.

Gastric adenocarcinoma is a highly aggressive disease with poor overall survival. The aggressive nature of this disease is in part due to the high intra and inter tumoral heterogeneity and also due to the late diagnosis at presentation. Once progression occurs, treatment is more difficult due to the adaptation of tumors, which acquires resistance to commonly used chemotherapeutics.

Calcium Release-Activated Calcium (CRAC) Channel Inhibition Suppresses Pancreatic Ductal Adenocarcinoma Cell Proliferation and Patient-Derived Tumor Growth.

Pancreatic ductal adenocarcinoma (PDAC) remains an unmet clinical problem in urgent need of newer molecularly driven treatment modalities. Calcium signals, particularly those associated with calcium release-activated calcium (CRAC) channels, are known to influence the development, growth, and metastasis of many cancers. This is the first study investigating the impact of CRAC channel inhibition on PDAC cell lines and patient-derived tumor models.

Gut microbiome and response to checkpoint inhibitors in non-small cell lung cancer-A review.

The gut microbiome is a collection of diverse bacteria that normally reside within the gastrointestinal tract. In recent years, the relationship between the gut microbiome, and fluctuations in it, and overall health has been an intense area of interest in medical research. In addition to having a barrier role in the gastrointestinal tract, there appears to be an immune function of gut microbiota, with a correlation between dysbiosis of gut microbiota and certain inflammatory and malignant disease states of the gastrointestinal system.

Targeting Nuclear Exporter Protein XPO1/CRM1 in Gastric Cancer.

Gastric cancer remains an unmet clinical problem in urgent need of newer and effective treatments. Here we show that the nuclear export protein, Exportin 1 (XPO1, chromosome region maintenance 1 or CRM1), is a promising molecular target in gastric cancer. We demonstrate significant overexpression of XPO1 in a cohort of histologically diverse gastric cancer patients with primary and metastatic disease.

Ras and exosome signaling.

Ras gene (HRAS, NRAS, and KRAS) has been observed to be mutated and hyper-activated in a significant proportion of cancers. However, mutant Ras remains a challenging therapeutic target. Similarly, inhibition of targets upstream and downstream of Ras has shown limited clinical utility.

Metabotropic glutamate receptor-1 regulates inflammation in triple negative breast cancer.

Breast cancer remains a major cause of death among women. 15% of these cancers are triple negative breast cancer (TNBC), an aggressive subtype of breast cancer for which no current effective targeted therapy exists. We have previously demonstrated a role for mGluR1 in mediating tumor cell growth, endothelial cell proliferation, and tumor-induced angiogenesis in TNBC.

Kinetics of nucleotide entry into RNA polymerase active site provides mechanism for efficiency and fidelity.

During transcription, RNA polymerase II elongates RNA by adding nucleotide triphosphates (NTPs) complementary to a DNA template. Structural studies have suggested that NTPs enter and exit the active site via the narrow secondary pore but details have remained unclear. A kinetic model is presented that integrates molecular dynamics simulations with experimental data.

A phase II trial of BAY 43-9006 (sorafenib) (NSC-724772) in patients with relapsing and resistant multiple myeloma: SWOG S0434.

The authors assessed the overall response rate, including confirmed complete response (CR) and partial response, in patients with relapsed/refractory multiple myeloma treated with sorafenib. Qualitative and quantitative toxicities associated with this regimen were evaluated. Patients were eligible if they had a confirmed diagnosis of refractory or relapsed (RR) multiple myeloma (MM) with measurable monoclonal protein.

Second malignancies in total therapy 2 and 3 for newly diagnosed multiple myeloma: influence of thalidomide and lenalidomide during maintenance.

Thalidomide and lenalidomide constitute an important part of effective myeloma therapy. Recent data from the Intergroup Francophone du Myélome, Cancer and Leukemia Group B, and Gruppo Italiano Malattie Ematologiche dell Adulto MM-015 trials suggest that lenalidomide maintenance therapy is associated with a higher incidence of second primary malignancies (SPMs), including both hematologic and solid malignancies. In the present study, we analyzed data from the Total Therapy 2 (TT2) trial, along with the 2 Total Therapy 3 (TT3) trials.

Autologous stem cell transplantation as a care option in Waldenström's macroglobulinemia.

The optimal management of Waldenstrom's macroglobulinemia (WM) is in evolution, especially since the introduction of novel agents for its sister disease, multiple myeloma. Literature on the utility of autologous stem cell transplantation (ASCT) in WM, albeit mostly retrospective, supports its efficacy for symptomatic disease in eligible patients. Here, we present the experience of managing WM at our single institution.