Paradoxical Activation of Oncogenic Signaling as a Cancer Treatment Strategy.

Cancer homeostasis depends on a balance between activated oncogenic pathways driving tumorigenesis and engagement of stress response programs that counteract the inherent toxicity of such aberrant signaling. Although inhibition of oncogenic signaling pathways has been explored extensively, there is increasing evidence that overactivation of the same pathways can also disrupt cancer homeostasis and cause lethality. We show here that inhibition of protein phosphatase 2A (PP2A) hyperactivates multiple oncogenic pathways and engages stress responses in colon cancer cells.

An LC-MS/MS method for simultaneous determination of LB-100 and its active metabolite, endothall, in human plasma.

We have developed and validated a novel LC-MS/MS method for the simultaneous quantification of LB-100 and its active metabolite, endothall, in human plasma following solid-phase extraction. LB-105 and endothall-D6 were used as internal standards. Chromatographic separation was achieved on a Hypercarb™ column using 5 mM (NH)CO and 30:70 (v/v) 100 mM (NH)CO:acetonitrile as mobile phases.

Protein Phosphatase 2A as a Therapeutic Target in Small Cell Lung Cancer.

Protein phosphatase 2A (PP2A), a serine/threonine phosphatase involved in the regulation of apoptosis, proliferation, and DNA-damage response, is overexpressed in many cancers, including small cell lung cancer (SCLC). Here we report that LB100, a small molecule inhibitor of PP2A, when combined with platinum-based chemotherapy, synergistically elicited an antitumor response both and with no apparent toxicity. Using inductively coupled plasma mass spectrometry, we determined quantitatively that sensitization via LB100 was mediated by increased uptake of carboplatin in SCLC cells.

Inhibition of protein phosphatase-2A with LB-100 enhances antitumor immunity against glioblastoma.

Purpose: Glioblastoma (GBM) carries a dismal prognosis despite standard multimodal treatment with surgery, chemotherapy and radiation. Immune checkpoint inhibitors, such as PD1 blockade, for treatment of GBM failed to show clinical benefit. Rational combination strategies to overcome resistance of GBM to checkpoint monotherapy are needed to extend the promise of immunotherapy to GBM management.

Inhibition of PP2A with LB-100 Enhances Efficacy of CAR-T Cell Therapy Against Glioblastoma.

Chimeric antigen receptor (CAR)-engineered T cells represent a promising modality for treating glioblastoma. Recently, we demonstrated that CAR-T cells targeting carbonic anhydrase IX (CAIX), a protein involved in HIF-1a hypoxic signaling, is a promising CAR-T cell target in an intracranial murine glioblastoma model. Anti-CAIX CAR-T cell therapy is limited by its suboptimal activation within the tumor microenvironment.

Pharmacologic inhibition of protein phosphatase-2A achieves durable immune-mediated antitumor activity when combined with PD-1 blockade.

Mounting evidence suggests that inhibition of protein phosphatase-2A (PP2A), a serine/threonine phosphatase, could enhance anticancer immunity. However, drugs targeting PP2A are not currently available. Here, we report that a PP2A inhibitor, LB-100, when combined with anti-PD-1 (aPD-1) blockade can synergistically elicit a durable immune-mediated antitumor response in a murine CT26 colon cancer model.

Safety, Tolerability, and Preliminary Activity of LB-100, an Inhibitor of Protein Phosphatase 2A, in Patients with Relapsed Solid Tumors: An Open-Label, Dose Escalation, First-in-Human, Phase I Trial.

To determine the MTD and to assess the safety, tolerability, and potential activity of LB-100, a first-in-class small-molecule inhibitor of protein phosphatase 2A (PP2A) in adult patients with progressive solid tumors. LB-100 was administered intravenously daily for 3 days in 21-day cycles in a 3 + 3 dose escalation design. There were 29 patient entries over 7 dose escalations.

The relationship between body iron stores and blood and urine cadmium concentrations in US never-smoking, non-pregnant women aged 20-49 years.

Background: Cadmium is a ubiquitous environmental pollutant associated with increased risk of leading causes of mortality and morbidity in women, including breast cancer and osteoporosis. Iron deficiency increases absorption of dietary cadmium, rendering women, who tend to have lower iron stores than men, more susceptible to cadmium uptake. We used body iron, a measure that incorporates both serum ferritin and soluble transferrin receptor, as recommended by the World Health Organization, to evaluate the relationships between iron status and urine and blood cadmium.

Environmental cadmium and breast cancer risk.

Breast cancer is the most prevalent women's cancer, with an age-adjusted incidence of 122.9 per 100,000 US women. Cadmium, a ubiquitous carcinogenic pollutant with multiple biological effects, has been reported to be associated with breast cancer in one US regional case-control study.

Cadmium, follicle-stimulating hormone, and effects on bone in women age 42-60 years, NHANES III.

Background: Increased body burden of environmental cadmium has been associated with greater risk of decreased bone mineral density (BMD) and osteoporosis in middle-aged and older women, and an inverse relationship has been reported between follicle-stimulating hormone (FSH) and BMD in middle-aged women; however, the relationships between cadmium and FSH are uncertain, and the associations of each with bone loss have not been analyzed in a single population.

Objectives: The objective of this study was to evaluate the associations between creatinine-adjusted urinary cadmium (UCd) and FSH levels, and the associations between UCd and FSH with BMD and osteoporosis, in postmenopausal and perimenopausal women aged 42-60 years.

Methods: Data were obtained from the Third National Health Examination and Nutrition Survey, 1988-1994 (NHANES III).

Enhancement of cancer chemotherapy by simultaneously altering cell cycle progression and DNA-damage defenses through global modification of the serine/threonine phospho-proteome.

Despite improvements in the therapeutic efficacy of rationally designed cancer treatment regimens, most cancers remain incurable once spread beyond their sites of origin. Failure to achieve sustained control or eradication of cancers arises in large part because a subpopulation of quiescent "cancer stem cells" is insensitive to drugs targeting cell growth and replication and because defense mechanisms critical to survival of the normal cell also protect the cancer cell from cytotoxic injury. Global alteration of signal transduction by inhibition of serine/threonine dephosphorylation has recently been shown to markedly potentiate cancer cell killing by the DNA-methylating drug, temozolomide.

Inhibition of serine/threonine phosphatase PP2A enhances cancer chemotherapy by blocking DNA damage induced defense mechanisms.

A variety of mechanisms maintain the integrity of the genome in the face of cell stress. Cancer cell response to chemotherapeutic and radiation-induced DNA damage is mediated by multiple defense mechanisms including polo-like kinase 1 (Plk-1), protein kinase B (Akt-1), and/or p53 pathways leading to either apoptosis or cell cycle arrest. Subsequently, a subpopulation of arrested viable cancer cells may remain and recur despite aggressive and repetitive therapy.

Urinary cadmium and osteoporosis in U.S. Women >or= 50 years of age: NHANES 1988-1994 and 1999-2004.

Background: Urinary cadmium (U-Cd) has been associated with decreased peripheral bone mineral density (BMD) and osteoporosis. This association, however, has not been confirmed using femoral BMD, the international standard for diagnosing osteoporosis, at levels < 1.0 microg Cd/g creatinine.

Detection of cancer-specific markers amid massive mass spectral data.

We propose a comprehensive pattern recognition procedure that will achieve best discrimination between two or more sets of subjects with data in the same coordinate system. Applying the procedure to MS data of proteomic analysis of serum from ovarian cancer patients and serum from cancer-free individuals in the Food and Drug Administration/National Cancer Institute Clinical Proteomics Database, we have achieved perfect discrimination (100% sensitivity, 100% specificity) of patients with ovarian cancer, including early-stage disease, from normal controls for two independent sets of data. Our procedure identifies the best subset of proteomic biomarkers for optimal discrimination between the groups and appears to have higher discriminatory power than other methods reported to date.