Modeling Precursor Lesions by Targeting Key Molecular Pathways in High-Grade Serous Ovarian Cancer

High-Grade Serous Ovarian Cancer (HGSC) is the deadliest gynecological malignancy that affects women worldwide. A major confounding factor in the field is that the epithelial subtype responsible for HGSC is unclear and could either be the ovarian surface epithelium (OSE) or the fallopian tube epithelium (FTE) or both. Regardless of organ site, elevated levels of gonadotropin hormones are associated with increased incidence of ovarian cancer. Gonadotropins increased proliferation in both 3D ovarian organ culture and in a 2D normal mouse OSE cell line. Activation of pathways, such as Akt, EGFR, Birc5, Cdk2, Cdk4, and Cdkn2a identified in the 3D organ cultures, were also validated in 2D MOSE cells. Akt and EGFR inhibitors blocked gonadotropin-induced cell proliferation in 3D organ and 2D cell culture. These data suggested that the gonadotropins stimulate some of the same proliferative pathways in normal OSE that are activated in ovarian cancers. Rapid advances have been made in modeling serous pathogenesis from the FTE. However, the existing models fail to recapitulate the molecular basis of early precursor lesion development from the FTE. Loss of PAX2 is one of the earliest reported changes identified in the FTE that may define the transition of the normal FTE into benign lesions. Combination of PAX2 loss and mutant TP53 in murine oviductal epithelium (MOE) cells altered functional characteristics in vitro but was insufficient to drive tumorigenesis in vivo. Re-expression of PAX2 in PAX2-null human HGSC cells reduced tumorigenic properties via apoptosis. Reduced levels of PTEN negatively regulated PAX2 expression in MOE cells and stable re-expression of PAX2 reduced the tumorigenic effects from PTEN silencing. A novel biological screen identified a molecule that can activate PAX2 expression in MOE cells. A novel targeted delivery system conjugated to Follicle Stimulating Hormone (FSH) peptide was designed to specifically target FSH receptor in ovarian cancer cells. The selectivity of the FSH-targeted dendrimers was validated in 3D ovarian organ cultures, in vivo and in a HGSC cell line. In summary, it is critical to determine the mechanism of early precursor formation and design delivery systems to accurately target ovarian cancer cells

Gonadotropins Activate Oncogenic Pathways to Enhance Proliferation in Normal Mouse Ovarian Surface Epithelium

Ovarian cancer is the most lethal gynecological malignancy affecting American women. The gonadotropins, follicle stimulating hormone (FSH) and luteinizing hormone (LH), have been implicated as growth factors in ovarian cancer. In the present study, pathways activated by FSH and LH in normal ovarian surface epithelium (OSE) grown in their microenvironment were investigated. Gonadotropins increased proliferation in both three-dimensional (3D) ovarian organ culture and in a two-dimensional (2D) normal mouse cell line. A mouse cancer pathway qPCR array using mRNA collected from 3D organ cultures identified Akt as a transcriptionally upregulated target following stimulation with FSH, LH and the combination of FSH and LH. Activation of additional pathways, such as Birc5, Cdk2, Cdk4, and Cdkn2a identified in the 3D organ cultures, were validated by western blot using the 2D cell line. Akt and epidermal growth factor receptor (EGFR) inhibitors blocked gonadotropin-induced cell proliferation in 3D organ and 2D cell culture. OSE isolated from 3D organ cultures stimulated with LH or hydrogen peroxide initiated growth in soft agar. Hydrogen peroxide stimulated colonies were further enhanced when supplemented with FSH. LH colony formation and FSH promotion were blocked by Akt and EGFR inhibitors. These data suggest that the gonadotropins stimulate some of the same proliferative pathways in normal OSE that are activated in ovarian cancers

Investigation of depression,life satisfaction and related factors of the elderly in Sichuan earthquake area

目的探讨5.12地震灾区老年人的抑郁情绪、生活满意度及其相关因素。方法5.12地震后8个月,采用Scl-90抑郁分量表、躯体化分量表、生活满意度量表以及心理韧性量表和社会支持量表对灾区的70名老年组被试和139名青年对照组被试进行施测。结果灾区老年人的抑郁得分略高于青年人(t=1.68,P=0.09),躯体化得分显著高于青年人(t=3.198,P<0.01),生活满意度得分显著高于青年人(t=6.20,P<0.001),老年人的心理韧性得分也显著高于青年人(t=3.11,P<0.01),而社会支持得分显著低于青年人(t=-3.29,P<0.01);心理韧性正向预测生活满意度(β=0.34,P<0.001),而与抑郁、躯体化无关,社会支持负向预测抑郁情绪(β=-0.33,P<0.001),同时正向预测生活满意度(β=0.19,P<0.001)和韧性(β=0.22,P<0.001)。结论与灾区青年人相比,灾区老年人同时表现出较高的抑郁情绪、躯体化和较高的生活满意度,这与老年人拥有较低的社会支持和较高的心理韧性有关,但心理韧性并不能帮助他们缓解抑郁情绪和躯体化,甚至还受到社会支持减少的潜在影响

A phase 1 study of the pan-bromodomain and extraterminal inhibitor mivebresib (ABBV-075) alone or in combination with venetoclax in patients with relapsed/refractory acute myeloid leukemia.

BackgroundAcute myeloid leukemia (AML) is a heterogenous malignancy driven by genetic and epigenetic factors. Inhibition of bromodomain and extraterminal (BET) proteins, epigenetic readers that play pivotal roles in the regulation of genes relevant to cancer pathogenesis, constitutes a novel AML treatment approach.MethodsIn this first-in-human study of the pan-BET inhibitor mivebresib as monotherapy (MIV-mono) or in combination with venetoclax (MIV-Ven), the safety profile, efficacy, and pharmacodynamics of mivebresib were determined in patients with relapsed/refractory AML (ClinicalTrials.gov identifier NCT02391480). Mivebresib was administered at 3 monotherapy dose levels (1.5, 2.0, or 2.5 mg) or in combination with venetoclax (400 or 800 mg).ResultsForty-four patients started treatment: of 19 who started MIV-mono, 5 went on to receive MIV-Ven combination therapy after disease progression and a washout period. Twenty-five patients started MIV-Ven, resulting in a total of 30 patients treated with the combination. The most common mivebresib-related treatment-emergent adverse events were dysgeusia (74%), decreased appetite (42%), and diarrhea (42%) in the MIV-mono group and decreased appetite (44%), vomiting (44%), and nausea (40%) in the MIV-Ven group. Serious adverse events occurred in 14 patients (74%) who received MIV-mono and in 22 patients (88%) who received MIV-Ven. In the MIV-mono group, responses were complete remission with incomplete blood count recovery in 1 patient and resistant disease in 15 patients. In the MIV-Ven group, responses were complete remission in 2 patients, partial remission in 2 patients, morphologic leukemia-free state in 2 patients, resistant disease in 12 patients, and aplasia in 1 patient. The pharmacodynamic effects of mivebresib were proportional to dose and drug exposure.ConclusionsMivebresib was tolerated and showed antileukemic effects as monotherapy and in combination with venetoclax in patients with relapsed/refractory AML.Lay summaryMivebresib is a novel drug that influences the way cancer cells read genetic information. Mivebresib was tested together with venetoclax in patients with acute myeloid leukemia after standard medicines failed and the disease returned, or when standard medicine was unavailable. Adverse effects were described for different drug doses, and the dose that is tolerable was determined. In some patients, their leukemia improved for some time. More studies are necessary to determine whether mivebresib can be used to treat acute myeloid leukemia

Eftozanermin alfa (ABBV-621) monotherapy in patients with previously treated solid tumors: findings of a phase 1, first-in-human study

Eftozanermin alfa (eftoza), a second-generation tumor necrosis factor-related apoptosis-inducing ligand receptor (TRAIL-R) agonist, induces apoptosis in tumor cells by activation of death receptors 4/5. This phase 1 dose-escalation/dose-optimization study evaluated the safety, pharmacokinetics, pharmacodynamics, and preliminary activity of eftoza in patients with advanced solid tumors. Patients received eftoza 2.5–15 mg/kg intravenously on day 1 or day 1/day 8 every 21 days in the dose-escalation phase, and 1.25–7.5 mg/kg once-weekly (QW) in the dose-optimization phase. Dose-limiting toxicities (DLTs) were evaluated during the first treatment cycle to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D). Pharmacodynamic effects were evaluated in circulation and tumor tissue. A total of 105 patients were enrolled in the study (dose-escalation cohort, n = 57; dose-optimization cohort, n = 48 patients [n = 24, colorectal cancer (CRC); n = 24, pancreatic cancer (PaCA)]). In the dose-escalation cohort, seven patients experienced DLTs. MTD and RP2D were not determined. Most common treatment-related adverse events were increased alanine aminotransferase and aspartate aminotransferase levels, nausea, and fatigue. The one treatment-related death occurred due to respiratory failure. In the dose-optimization cohort, three patients (CRC, n = 2; PaCA, n = 1) had a partial response. Target engagement with regard to receptor saturation, and downstream apoptotic pathway activation in circulation and tumor were observed. Eftoza had acceptable safety, evidence of pharmacodynamic effects, and preliminary anticancer activity. The 7.5-mg/kg QW regimen was selected for future studies on the basis of safety findings, pharmacodynamic effects, and biomarker modulations. (Trial registration number: NCT03082209 (registered: March 17, 2017))

Activity of eftozanermin alfa plus venetoclax in preclinical models and patients with acute myeloid leukemia

Activation of apoptosis in malignant cells is an established strategy for controlling cancer and is potentially curative. To assess the impact of concurrently inducing the extrinsic and intrinsic apoptosis-signaling pathways in acute myeloid leukemia (AML), we evaluated activity of the TRAIL receptor agonistic fusion protein eftozanermin alfa (eftoza; ABBV-621) in combination with the B-cell lymphoma protein-2 selective inhibitor venetoclax in preclinical models and human patients. Simultaneously stimulating intrinsic and extrinsic apoptosis-signaling pathways with venetoclax and eftoza, respectively, enhanced their activities in AML cell lines and patient-derived ex vivo/in vivo models. Eftoza activity alone or plus venetoclax required death receptor 4/5 (DR4/DR5) expression on the plasma membrane but was independent of TP53 or FLT3-ITD status. The safety/tolerability of eftoza as monotherapy and in combination with venetoclax was demonstrated in patients with relapsed/refractory AML in a phase 1 clinical trial. Treatment-related adverse events were reported in 2 of 4 (50%) patients treated with eftoza monotherapy and 18 of 23 (78%) treated with eftoza plus venetoclax. An overall response rate of 30% (7/23; 4 complete responses [CRs], 2 CRs with incomplete hematologic recovery, and 1 morphologic leukemia-free state) was reported in patients who received treatment with eftoza plus venetoclax and 67% (4/6) in patients with myoblasts positive for DR4/DR5 expression; no tumor responses were observed with eftoza monotherapy. These data indicate that combination therapy with eftoza plus venetoclax to simultaneously activate the extrinsic and intrinsic apoptosis-signaling pathways may improve clinical benefit compared with venetoclax monotherapy in relapsed/refractory AML with an acceptable toxicity profile. This trial was registered at www.clinicaltrials.gov as #NCT03082209.</p

Co-clinical Modeling of the Activity of the BET Inhibitor Mivebresib (ABBV-075) in AML

Background/aimThe therapeutic potential of bromodomain and extra-terminal motif (BET) inhibitors in hematological cancers has been well established in preclinical and early-stage clinical trials, although as of yet, no BETtargeting agent has achieved approval. To add insight into potential response to mivebresib (ABBV-075), a broadspectrum BET inhibitor, co-clinical modeling of individual patient biopsies was conducted in the context of a Phase I trial in acute myeloid leukemia (AML).Materials and methodsCo-clinical modeling involves taking the patient's biopsy and implanting it in mice with limited passage so that it closely retains the original characteristics of the malignancy and allows comparisons of response between animal model and clinical data. Procedures were developed, initially with neonate NOD/Shi-scid-IL2rγnull (NOG) mice and then optimized with juvenile NOG-EXL as host mice, eventually resulting in a robust rate of engraftment (16 out of 26, 62%).ResultsResults from the co-clinical AML patient-derived xenograft (PDX) modeling (6 with &gt;60% inhibition of bone marrow blasts) were consistent with the equivalent clinical data from patients receiving mivebresib in monotherapy, and in combination with venetoclax. The modeling system also demonstrated the activity of a novel BD2-selective BET inhibitor (ABBV-744) in the preclinical AML setting. Both agents were also highly effective in inhibiting blast counts in the spleen (10/10 and 5/6 models, respectively).ConclusionThese findings confirm the validity of the model system in the co-clinical setting, establish highly relevant in vivo models for the discovery of cancer therapy, and indicate the therapeutic value of BET inhibitors for AML and, potentially, myelofibrosis treatment