Constitutively decreased TGFBR1 allelic expression is a common finding in colorectal cancer and is associated with three TGFBR1 SNPs

Purpose: Constitutively decreased TGFBR1 allelic expression is emerging as a potent modifier of colorectal cancer risk in mice and humans. This phenotype was first observed in mice, then in lymphoblastoid cell lines from patients with microsatellite stable colorectal tumors. Patients and Methods: We assessed the frequency of constitutively decreased TGFBR1 allelic expression and association with SNPs covering the TGFBR1 locus using RNA and DNA extracted from the peripheral blood lymphocytes of 118 consecutive patients with biopsy-proven adenocarcinoma of the colon or the rectum. Results: We found that 11(9.3%) of 118 patients exhibited decreased TGFBR1 allelic expression (TGFBR1 ASE). TGFBR1 ASE was strongly associated with three SNPs in linkage disequilibrium with each other: rs7034462 (p = 7.2 × 10-4), TGFBR1*6A (p = 1.6 × 10-4) and rs11568785 (p = 1.4 × 10-4). Conclusion: These results confirm the high prevalence of constitutively decreased TGFBR1 allelic expression among patients with colorectal cancer. The association of this phenotype with TGFBR1*6A, rs7034462 and rs1156875 suggests an association between TGFBR1 SNPs and colorectal cancer, which warrants additional studies

14-3-3τ Regulates Ubiquitin-Independent Proteasomal Degradation of p21, a Novel Mechanism of p21 Downregulation in Breast Cancer▿ †

14-3-3 proteins regulate many cellular functions, including proliferation. However, the detailed mechanisms by which they control the cell cycle remain to be fully elucidated. We report that one of the 14-3-3 isoforms, 14-3-3τ, is required for the G1/S transition through its role in ubiquitin-independent proteasomal degradation of p21. 14-3-3τ binds to p21, MDM2, and the C8 subunit of the 20S proteasome in G1 phase and facilitates proteasomal targeting of p21. This function of 14-3-3τ may be deregulated in cancer. The overexpression of 14-3-3τ is frequently found in primary human breast cancer and correlates with lower levels of p21 and shorter patient survival. Tenascin-C, an extracellular matrix protein involved in tumor initiation and progression and a known 14-3-3τ inducer, decreases p21 and abrogates adriamycin-induced G1/S arrest. It has been known that p21 is required for a proper tamoxifen response in breast cancer. We show that the overexpression of 14-3-3τ inhibits tamoxifen-induced p21 induction and growth arrest in MCF7 cells. Together, the findings of our studies strongly suggest a novel oncogenic role of 14-3-3τ by downregulating p21 in breast cancer. Therefore, 14-3-3τ may be a potential therapeutic target in breast cancer

Regulation of p53 by TopBP1: a Potential Mechanism for p53 Inactivation in Cancer▿ †

Proper control of the G1/S checkpoint is essential for normal proliferation. The activity of p53 must be kept at a very low level under unstressed conditions to allow growth. Here we provide evidence supporting a crucial role for TopBP1 in actively repressing p53. Depletion of TopBP1 upregulates p53 target genes involved in cell cycle arrest and apoptosis and enhances DNA damage-induced apoptosis. The regulation is mediated by an interaction between the seventh and eighth BRCT domains of TopBP1 and the DNA-binding domain of p53, leading to inhibition of p53 promoter binding activity. Importantly, TopBP1 overexpression is found in 46 of 79 primary breast cancer tissues and is associated with high tumor grade and shorter patient survival time. Overexpression of TopBP1 to a level comparable to that seen in breast tumors leads to inhibition of p53 target gene expression and DNA damage-induced apoptosis and G1 arrest. Thus, a physiological level of TopBP1 is essential for normal G1/S transition, but a pathological level of TopBP1 in cancer may perturb p53 function and contribute to an aggressive tumor behavior

Phase 1b Study of TRU-016, an Anti-CD37 SMIP™ Protein, in Combination with Rituximab and Bendamustine in Relapsed Indolent Lymphoma

Abstract 3678 Background: CD37 is a tetraspanin protein expressed on the surface of normal and transformed B-cells across a wide range of maturational stages and demonstrates death signaling via SHP1. TRU-016 is a novel humanized anti-CD37 SMIP™ (mono-specific protein therapeutic) that has shown significantly greater direct killing of CLL cells than rituximab and greater Fc mediated cellular cytotoxicity of CLL cells than either alemtuzumab or rituximab in pre-clinical models. In preclinical in vitro and in vivo models of NHL significant activity of TRU-016 against multiple cell lines was observed. In a phase 1 study, TRU-016 showed activity in patients (pts) with CLL and NHL was observed. Given the single-agent clinical activity of TRU-016 and synergistic or additive effect of TRU-016 with multiple agents in preclinical models, this trial of TRU-016 with rituximab and bendamustine was conducted to establish the maximum tolerated dose, overall safety, and clinical activity of TRU-016 in pts with relapsed indolent NHL. Methods: Pts with relapsed or refractory indolent B-cell NHL with adequate organ function, ECOG ≤2, absolute neutrophil count ≥1000/μL, platelets9100,000/μL who were not refractory to bendamustine were eligible. After premedication with acetaminophen, diphenhydramine, and hydrocortisone pts received TRU-016 (10 or 20 mg/kg on Days 1 and 15) over 2–3 hrs combined with rituximab 375 mg/m 2 (Day 2) and bendamustine 90 mg/m 2 (Days 1 and 2) by IV infusion for up to six 28-day cycles. Safety was evaluated using CTCAE 4.03 and response was determined using the Revised Response Criteria for Malignant Lymphoma (Cheson 2007) after every 2 cycles. Results: 12 pts, (9 with follicular lymphoma (FL) and 3 with small lymphocytic lymphoma (SLL)) were treated (6 each dose level). Pt characteristics: median age 57 yrs (range, 51–79), median prior regimens 3 (1–4), 67% ≥ stage III at diagnosis, 4 pts had bulky disease > 5cm. All pts had relapsed after prior rituximab (R) including 3 refractory to their most recent previous treatment. In addition, prior treatments included: CHOP-R (8), RICE (5), single agent R (5), transplant (2). FLIPI scores at study entry (FL pts) were: 8 intermediate, 1 low. The most frequent (>2 pts) adverse events (AEs) were: neutropenia (8), fatigue, nausea, insomnia, and WBC decreased (7 each); anemia, diarrhea, headache, hypophosphatemia, thrombocytopenia, and vomiting (3 each). Grade 3/4 AEs that occurred in >1 pt were neutropenia (6), hypophosphatemia (3), WBC decreased (2). Serious AEs (SAE) included asymptomatic pulmonary thrombosis in 2 pts and febrile neutropenia, pneumonia, myelodysplastic syndrome (pt had prior transplant, CHOP, RICE), deep vein thrombosis, and retinal vein occlusion (last 2 events and pulmonary thrombosis occurred in same pt) in 1 pt each. There was no apparent dose relationship to the SAEs. The best overall response was 10/12 (83%) with 4 CRs (32%). Four responding pts (1 CR, 3 PR) discontinued treatment prior to cycle 6 due to undergoing consolidation with transplant (2), development of myelodysplastic syndrome (1), and delayed neutrophil recovery (1). The 4 discontinuations occurred in the 20 mg cohort and limit the response evaluation of the 20 mg dose. However, after Cycle 2 Day 15, the overall response rate was 67% at 10 mg/kg and 100% at 20 mg/kg. Three of the 4 pts with bulky disease responded to the regimen Conclusions: TRU-016 in combination with rituximab and bendamustine was well-tolerated, induces responses in the majority of patients with relapsed indolent B-NHL. A MTD was not defined. Future combination studies of TRU-016 in NHL are warranted. Disclosures: Mato: Celgene, Milennium, Genentech, Seattle Genetics: Speakers Bureau. Stromatt: Emergent Product Development: Employment

Phase 1b study of otlertuzumab (TRU-016), an anti-CD37 monospecific ADAPTIR™ therapeutic protein, in combination with rituximab and bendamustine in relapsed indolent lymphoma patients

PURPOSE: CD37 is cell surface tetraspanin present on normal and malignant B cells. Otlertuzumab (TRU-016) is a novel humanized anti-CD37 protein therapeutic that triggers direct caspase independent apoptosis of malignant B cells and induces antibody-dependent cell-mediated cytotoxicity. This study evaluated the safety, pharmacokinetics, and efficacy of otlertuzumab administered in combination with rituximab and bendamustine to patients with relapsed, indolent B-cell non-Hodgkin Lymphoma (NHL). METHODS: Patients with relapsed or refractory NHL received otlertuzumab (10 or 20 mg/kg) intravenously (IV) on days 1 and 15, bendamustine (90 mg/m(2)) on days 1 and 2, and rituximab (375 mg/m(2)) on day 1 for up to six 28 day cycles. Responses were determined using standard criteria. RESULTS: Twelve patients were treated with 6 patients at each dose level; median age was 57 years (range, 51–79), and median number of prior regimens was 3 (range, 1–4). All patients had relapsed after prior rituximab including 7 refractory to their most recent previous treatment. In the 10 and 20 mg/kg dose cohorts, the mean half-life was 8 and 10 days following the first dose, and 12 or 14 days following 12 doses of otlertuzumab, respectively. Overall response rate was 83 % (10/12) with 4 CRs (32 %). The most frequent adverse events were neutropenia, nausea, fatigue, leukopenia, and insomnia; most were grade 1 or 2. CONCLUSIONS: Otlertuzumab in combination with rituximab and bendamustine was well tolerated and induced responses in the majority of patients with relapsed indolent B-NHL