Haploinsufficiency for p190B RhoGAP inhibits MMTV-Neu tumor progression

Introduction: Rho signaling regulates key cellular processes including proliferation, survival, and migration, and it has been implicated in the development of many types of cancer including breast cancer. P190B Rho GTPase activating protein (RhoGAP) functions as a major inhibitor of the Rho GTPases. P190B is required for mammary gland morphogenesis, and overexpression of p190B in the mammary gland induces hyperplastic lesions. Hence, we hypothesized that p190B may play a pivotal role in mammary tumorigenesis. Methods: To investigate the effects of loss of p190B function on mammary tumor progression, p190B heterozygous mice were crossed with an MMTV-Neu breast cancer model. Effects of p190B deficiency on tumor latency, multiplicity, growth, preneoplastic progression and metastasis were evaluated. To investigate potential differences in tumor angiogenesis between the two groups, immunohistochemistry to detect von Willebrand factor was performed and quantified. To examine gene expression of potential mediators of the angiogenic switch, an angiogenesis PCR array was utilized and results were confirmed using immunohistochemistry. Finally, reciprocal transplantation of tumor fragments was performed to determine the impact of stromal deficiency of p190B on tumor angiogenesis. Results: P190B deficiency reduced tumor penetrance (53% of $p190B^{+/-}Neu$ mice vs. 100% of $p190B^{+/+}Neu$ mice formed tumors) and markedly delayed tumor onset by an average of 46 weeks. Tumor multiplicity was also decreased, but an increase in the number of preneoplastic lesions was detected indicating that p190B deficiency inhibited preneoplastic progression. Angiogenesis was decreased in the p190B heterozygous tumors, and expression of a potent angiogenic inhibitor, thrombospondin-1, was elevated in $p190B^{+/-}Neu$ mammary glands. Transplantation of $p190B^{+/-}Neu$ tumor fragments into wild-type recipients restored tumor angiogenesis. Strikingly, $p190B^{+/+}Neu$ tumor fragments were unable to grow when transplanted into $p190B^{+/-}Neu$ recipients. Conclusions: These data suggest that p190B haploinsufficiency in the epithelium inhibits MMTV-Neu tumor initiation. Furthermore, p190B deficiency in the vasculature is responsible, in part, for the inhibition of MMTV-Neu tumor progression

Phase II study of the farnesyltransferase inhibitor R115777 in advanced melanoma (CALGB 500104)

BACKGROUND: Multiple farnesylated proteins are involved in signal transduction in cancer. Farnesyltransferase inhibitors (FTIs) have been developed as a strategy to inhibit the function of these proteins. As FTIs inhibit proliferation of melanoma cell lines, we undertook a study to assess the impact of a FTI in advanced melanoma. As farnesylated proteins are also important for T cell activation, measurement of effects on T cell function was also pursued. METHODS: A 3-stage trial design was developed with a maximum of 40 patients and early stopping if there were no responders in the first 14, or fewer than 2 responders in the first 28 patients. Eligibility included performance status of 0–1, no prior chemotherapy, at most 1 prior immunotherapy, no brain metastases, and presence of at least 2 cutaneous lesions amenable to biopsy. R115777 was administered twice per day for 21 days of a 28-day cycle. Patients were evaluated every 2 cycles by RECIST. Blood and tumor were analyzed pre-treatment and during week 7. RESULTS: Fourteen patients were enrolled. Two patients had grade 3 toxicities, which included myelosuppression, nausea/vomiting, elevated BUN, and anorexia. There were no clinical responses. All patients analyzed showed potent inhibition of FT activity (85-98%) in tumor tissue; inhibition of phosphorylated ERK and Akt was also observed. T cells showed evidence of FT inhibition and diminished IFN-γ production. CONCLUSIONS: Despite potent target inhibition, R115777 showed no evidence of clinical activity in this cohort of melanoma patients. Inhibition of T cell function by FTIs has potential clinical implications. Clinicaltrials.gov number NCT0006012

Pt···Pt vs Pt···S Contacts Between Pt-Containing Heterobimetallic Lantern Complexes

A trio of Pt-based heterobimetallic lantern complexes of the form [(py)­PtM­(SAc)₄(py)] (M = Co, <b>1</b>; Ni, <b>2</b>; Zn, <b>3</b>) with unusual octahedral coordination of Pt­(II) was prepared from a reaction of [PtM­(SAc)₄] with excess pyridine. These dipyridine lantern complexes could be converted to monopyridine derivatives with gentle heat to give the series [PtM­(SAc)₄(py)] (M = Co, <b>4</b>; Ni, <b>5</b>; Zn, <b>6</b>). An additional family of the form [PtM­(SAc)₄(pyNH₂)] (M = Co, <b>7</b>; Ni, <b>8</b>; Zn, <b>9</b>) was synthesized from reaction of [PtM­(SAc)₄(OH₂)] or [PtM­(SAc)₄] with 4-aminopyridine. Dimethylsulfoxide and <i>N</i>,<i>N</i>-dimethylformamide were also determined to react with [PtM­(SAc)₄] (M = Co, Ni), respectively, to give [PtCo­(SAc)₄(DMSO)]­(DMSO), <b>10</b>, and [PtNi­(SAc)₄(DMF)]­(DMF), <b>11</b>. Structural and magnetic data for these compounds and those for two other previously published families, [PtM­(tba)₄(OH₂)] and [PtM­(SAc)₄(L)], L = OH₂, pyNO₂, are used to divide the structures among three distinct categories based on Pt···Pt and Pt···S distances. In general, the weaker donors H₂O and pyNO₂ seem to favor metallophilicity and antiferromagnetic coupling between 3d metal centers. When Pt···S interactions are favored over Pt···Pt ones, no coupling is observed and the p<i>K</i>_a of the pyridine donor correlates with the interlantern S···S distance. UV–vis–NIR electronic and ¹H NMR spectra provide complementary characterization as well

Pt···Pt vs Pt···S Contacts Between Pt-Containing Heterobimetallic Lantern Complexes

A trio of Pt-based heterobimetallic lantern complexes of the form [(py)­PtM­(SAc)₄(py)] (M = Co, <b>1</b>; Ni, <b>2</b>; Zn, <b>3</b>) with unusual octahedral coordination of Pt­(II) was prepared from a reaction of [PtM­(SAc)₄] with excess pyridine. These dipyridine lantern complexes could be converted to monopyridine derivatives with gentle heat to give the series [PtM­(SAc)₄(py)] (M = Co, <b>4</b>; Ni, <b>5</b>; Zn, <b>6</b>). An additional family of the form [PtM­(SAc)₄(pyNH₂)] (M = Co, <b>7</b>; Ni, <b>8</b>; Zn, <b>9</b>) was synthesized from reaction of [PtM­(SAc)₄(OH₂)] or [PtM­(SAc)₄] with 4-aminopyridine. Dimethylsulfoxide and <i>N</i>,<i>N</i>-dimethylformamide were also determined to react with [PtM­(SAc)₄] (M = Co, Ni), respectively, to give [PtCo­(SAc)₄(DMSO)]­(DMSO), <b>10</b>, and [PtNi­(SAc)₄(DMF)]­(DMF), <b>11</b>. Structural and magnetic data for these compounds and those for two other previously published families, [PtM­(tba)₄(OH₂)] and [PtM­(SAc)₄(L)], L = OH₂, pyNO₂, are used to divide the structures among three distinct categories based on Pt···Pt and Pt···S distances. In general, the weaker donors H₂O and pyNO₂ seem to favor metallophilicity and antiferromagnetic coupling between 3d metal centers. When Pt···S interactions are favored over Pt···Pt ones, no coupling is observed and the p<i>K</i>_a of the pyridine donor correlates with the interlantern S···S distance. UV–vis–NIR electronic and ¹H NMR spectra provide complementary characterization as well

Erratum to: Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition) (Autophagy, 12, 1, 1-222, 10.1080/15548627.2015.1100356

non present