Citations

213 Background: Daily oral prednisone (P) has been employed for the therapy of mCRPC, alone or in combination regimens. Despite palliative benefits and PSA responses, the overall clinical impact of P is unknown and it may foster resistance mechanisms. We performed a pooled analysis of control arms of randomized trials which either did or did not administer single agent P to evaluate its impact on overall survival (OS) and toxicities. Methods: Individual patient data from control arms ofrandomized trials of post-docetaxel men receiving placebo or P + placebo were eligible for analysis. Patient demographics, survival, and toxicity data were collected. The impact of P on OS and toxicities was investigated in Cox regression models adjusted for known clinical and laboratory prognostic factors. Statistical significance was defined as a p-value < 0.05 and all tests were two-sided. Results: The control arms of 2 randomized phase III trials were available totaling 794 men: the COU-AA-301 trial (n = 394) administered P plus placebo and the CA184-043 trial (n = 400) administered placebo alone. P plus placebo was not significantly associated with OS compared to placebo alone in a multivariable analysis (HR = 0.89 [95% CI 0.72-1.10], p = 0.27). Other factors associated with poor OS were Eastern Cooperative Oncology group (ECOG)-performance status (PS) ≥ 1, Gleason Score ≥ 8, liver metastasis, high PSA, hypoalbuminemia, and elevated LDH.In contrast, CTCAE grade ≥ 3 therapy-related toxicities were significantly increased with P plus placebo compared to placebo alone (HR = 1.48 (1.03-2.13), p = 0.034) in a multivariable analysis. Other baseline factors significantly associated with a higher risk of grade ≥ 3 toxicities were ECOG-PS ≥ 1, hypoalbuminemia and elevated LDH. Conclusions: P plus placebo compared with placebo alone for post-docetaxel men with mCRPC was not associated with extension of OS, but was associated with higher grade ≥ 3 toxicities. With the exception of the use of P in combination with abiraterone, P alone or in combination regimens should be questioned given its unclear palliative benefits and association with increased toxicities.

Abstract Individual tumors, including the aggressive and difficult to treat triple-negative (ER-/PR-/HER2-) breast cancers (TNBCs) are heterogeneous collections of cells with multiple subclonal populations each contributing to the tumor. While subclonal heterogeneity is likely responsible for the development of drug resistance, identification of how tumor cell populations change over time has been difficult, largely because of the challenges in resampling tumor tissue at close time points. Here we quantify tumor evolution in human patient-derived xenografts implanted into NSG mice, which we use to test subclonal heterogeneity as a function of location within a tumor, propagation time, and drug treatment. We used high-depth (∼400x) sequencing of a targeted panel of 358 genes to quantify somatic mutation allele frequencies from 6 spatially-separated and 8 temporally-propagated xenograft samples derived from the same TNBC patient tumors. Samples ranged in age from 2-4 months post-engraftment. Although we observed a few low frequency mutations distinguishing samples, overall we found that allele frequencies of somatic mutations were well-preserved on this time scale. We then generated replicate xenografts from the same patient tumor and treated them respectively with cisplatin, doxorubicin, cyclophosphamide, docetaxel, or vehicle control for 25 days. Although again somatic mutations showed few differences in allele frequency across samples, substantial variations were seen when data were analyzed for copy number alterations. To confirm these effects we repeated the treatments for xenografts derived from two additional TNBC patients. Again we observed strong changes in tumor heterogeneity at the copy number level. This effect was particularly, but not exclusively, apparent in tumors with the greatest response to therapy. We further verified these measurements through Sanger and digital PCR sequencing on the treated mice and other mice in the same cohorts. Using a multi-sample xenograft propagation, dissection, sequencing, and computational analysis protocol, we have shown that tumor subpopulation changes in response to treatment can be quantified and distinguished from spatial or temporal effects, even for treatment time courses as short as 1 month. In triple negative breast cancer these variations are most apparent at the level of copy number variation. Our study demonstrates how patient-derived xenografts can provide detailed resolution of tumor population evolution during the manifestation of resistance. Citation Format: Hyunsoo Kim, Pooja Kumar, Francesca Menghi, Joshy George, Guru Ananda, Susan Mockus, Chengsheng Zhang, Nicholas Larson, Henry C. Chen, Yan Yang, James Keck, R. Krishnamurthy Karuturi, Charles Lee, Carol Bult, Edison Liu, Jeffrey H. Chuang. Evolution during propagation and treatment of patient-derived triple negative breast cancer xenografts. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2411.

A 64-year-old previously healthy man presented with a 4-week history of vague right upper quadrant abdominal pain. Imaging studies revealed extensive portal, splenic, superior and inferior mesenteric vein thrombosis with mosaic perfusion and wedge-shaped areas of liver perfusion abnormalities. An extensive thrombophilia workup including tests for factor V Leiden, prothrombin G20210A, lupus anticoagulant, paroxysmal nocturnal haemoglobinuria, protein C and S, homocysteine and antinuclear antibody titres were all negative. Other laboratory testing revealed an elevated alkaline phosphatase (340 IU/L). Surgical exploration and catheter-directed thrombolysis were not felt to be feasible given the extensive clot burden. He was started on anticoagulation therapy. Over the next 10 days, he required intensive care unit admission due to progressive hepatic encephalopathy and fulminant liver failure. He continued to decline and eventually died of multiorgan failure. Autopsy revealed extensive, diffuse intrahepatic cholangiocarcinoma that had almost entirely replaced his normal liver parenchyma.

Abstract Purpose: BNC105P inhibits tubulin polymerization, and preclinical studies suggest possible synergy with everolimus. In this phase I/II study, efficacy and safety of the combination were explored in patients with metastatic renal cell carcinoma (mRCC). Experimental Design: A phase I study in patients with clear cell mRCC and any prior number of therapies was conducted using a classical 3 + 3 design to evaluate standard doses of everolimus with increasing doses of BNC105P. At the recommended phase II dose (RP2D), patients with clear cell mRCC and one to two prior therapies (including ≥ 1 VEGF-TKI) were randomized to BNC105P with everolimus (arm A) or everolimus alone (arm B). The primary endpoint of the study was 6-month progression-free survival (6MPFS). Secondary endpoints included response rate, PFS, overall survival, and exploratory biomarker analyses. Results: In the phase I study (N = 15), a dose of BNC105P at 16 mg/m2 with everolimus at 10 mg daily was identified as the RP2D. In the phase II study, 139 patients were randomized, with 69 and 67 evaluable patients in arms A and B, respectively. 6MPFS was similar in the treatment arms (arm A: 33.82% vs. arm B: 30.30%, P = 0.66) and no difference in median PFS was observed (arm A: 4.7 mos vs. arm B: 4.1 mos; P = 0.49). Changes in matrix metalloproteinase-9, stem cell factor, sex hormone-binding globulin, and serum amyloid A protein were associated with clinical outcome with BNC105P. Conclusions: Although the primary endpoint was not met in an unselected population, correlative studies suggest several biomarkers that warrant further prospective evaluation. Clin Cancer Res; 21(15); 3420–7. ©2015 AACR.

The growing demand for reducing chemical inputs in agriculture and increased resistance to insecticides have provided great impetus to the development of alternative forms of insect-pest control. Myco-biocontrol offers an attractive alternative to the use of chemical pesticides. Myco-biocontrol agents are naturally occurring organisms which are perceived as less damaging to the environment. Their mode of action appears little complex which makes it highly unlikely that resistance could be developed to a biopesticide. Past research has shown some promise of the use of fungi as a selective pesticide. The current paper updates us about the recent progress in the field of myco-biocontrol of insect pests and their possible mechanism of action to further enhance our understanding about the biological control of insect pests.