Farshid Dayyani

Resistance to BRAF Inhibition in BRAF-Mutant Colon Cancer Can Be Overcome with PI3K Inhibition or Demethylating Agents

Purpose: Vemurafenib, a selective inhibitor of BRAFV600, has shown significant activity in BRAFV600 melanoma but not in less than 10% of metastatic BRAFV600 colorectal cancers (CRC), suggesting that studies of the unique hypermethylated phenotype and concurrent oncogenic activation of BRAFmut CRC may provide combinatorial strategies. Experimental Design: We conducted comparative proteomic analysis of BRAFV600E melanoma and CRC cell lines, followed by correlation of phosphoinositide 3-kinase (PI3K) pathway activation and sensitivity to the vemurafenib analogue PLX4720. Pharmacologic inhibitors and siRNA were used in combination with PLX4720 to inhibit PI3K and methyltransferase in cell lines and murine models. Results: Compared with melanoma, CRC lines show higher levels of PI3K/AKT pathway activation. CRC cell lines with mutations in PTEN or PIK3CA were less sensitive to growth inhibition by PLX4720 (P = 0.03), and knockdown of PTEN expression in sensitive CRC cells reduced growth inhibition by the drug. Combined treatment of PLX4720 with PI3K inhibitors caused synergistic growth inhibition in BRAF-mutant CRC cells with both primary and secondary resistance. In addition, methyltransferase inhibition was synergistic with PLX4720 and decreased AKT activation. In vivo, PLX4720 combined with either inhibitors of AKT or methyltransferase showed greater tumor growth inhibition than PLX4720 alone. Clones with acquired resistance to PLX4720 in vitro showed PI3K/AKT activation with EGF receptor (EGFR) or KRAS amplification. Conclusions: We show that activation of the PI3K/AKT pathway is a mechanism of both innate and acquired resistance to BRAF inhibitors in BRAFV600E CRC and suggest combinatorial approaches to improve outcomes in this poor prognosis subset of patients. Clin Cancer Res; 19(3); 657–67. ©2012 AACR.

Cause of death in patients with lower-risk myelodysplastic syndrome.

The authors have recently shown that a majority of patients with myelodysplastic syndrome (MDS) classified by the International Prognostic Scoring System as lower risk die without transformation to acute myelogenous leukemia (AML). The cause of death (COD) of these patients is not well understood. Identifying the COD could help to guide early therapy decisions.

Steps in prostate cancer progression that lead to bone metastasis

Prostate cancer is a complex disease in which metastasis to the bone is the main cause of death. Initial stages of metastasis are generally similar to those for most solid tumors; however, the mechanisms that underlie the homing of prostate tumor cells to the bone are not completely understood. Prostate cancer bone metastasis is also a microenvironment‐driven disease, involving bidirectional interactions between the tumor and the bone microenvironment. In this review, we discuss the current understanding of the biologic processes and regulatory factors involved in the metastasis of prostate cancer cells, and their specific properties that promote growth in bone. Although many of these processes still need to be fully elucidated, a better understanding of the complex tumor/microenvironment interplay is slowly leading to more effective therapies for patients with prostate cancer bone metastases.

Plasmacytoid Urothelial Carcinoma, a Chemosensitive Cancer with Poor Prognosis, and Peritoneal Carcinomatosis

PURPOSE Plasmacytoid urothelial carcinoma is a rare variant histology with poorly defined clinical behavior. We report clinical outcome information on patients with predominant plasmacytoid urothelial carcinoma. MATERIALS AND METHODS We retrospectively analyzed treatments and outcomes in patients with predominant plasmacytoid urothelial carcinoma seen at our institution from 1990 through 2010. The Kaplan-Meier method was used to calculate overall and progression-free survival. RESULTS We identified 31 patients with a median age of 63.5 years, of whom 83.3% were male. TNM stage was cT1N0 in 4 patients, cT2N0 in 7, cT3b-4aN0 in 5 and cT4b, N+ or M+ in 15. Median overall survival was 17.7 months (stage I-III vs IV 45.8 vs 13.3). Five of the 16 patients with potentially surgically resectable plasmacytoid urothelial carcinoma (pT4aN0M0 or less) received neoadjuvant chemotherapy, 10 underwent initial surgery and 1 was treated only with transurethral resection of bladder tumor. Despite pathological down staging in 80% of the patients who received neoadjuvant chemotherapy, relapses were common. There was no survival difference between patients treated with neoadjuvant chemotherapy or initial surgery, although 7 received adjuvant chemotherapy. Surgical up staging with positive margins was also common for surgery alone. The most common site of recurrence was in the peritoneum (19 of 23 patients) with relapses even in those with a pathological complete response at surgery. In patients who presented with metastatic disease and were treated with chemotherapy median survival was 12.6 months. CONCLUSIONS Plasmacytoid urothelial carcinoma is an aggressive subset with overall poor outcomes. Although down staging is seen with neoadjuvant chemotherapy, there are few long-term survivors. There is a strong predilection for recurrence along the peritoneal lining.

The role of HGF/c-Met signaling in prostate cancer progression and c-Met inhibitors in clinical trials

Introduction: An increasing number of basic, translational and clinical studies demonstrate the importance of the protein tyrosine kinase receptor, c-Met, in the progression of prostate cancer. c-Met is overexpressed in primary prostate cancers, further increased in expression in bone metastases and is associated with the development of castrate-resistant disease. Because of its importance as a target, c-Met inhibitors have reached clinical trial for advanced, castrate-resistant prostate cancer. Areas covered: In this review, altered expression of c-Met and hepatocyte growth factor in prostate tumors and the microenvironment and how they contribute to growth and invasion of prostate cancer cells is described. Next, preclinical studies providing the support for use of c-Met inhibitors are discussed. Finally, early promising results from c-Met inhibitors in clinical trial, and future prospects for c-Met inhibitors in the treatment of advanced stage prostate cancer, are discussed. Expert opinion: An emerging theme in treating metastatic prostate cancer is the requirement to target both the epithelial and stromal compartments. Results from clinical trials suggest that inhibitors of c-Met that block stromal-mediated c-Met activation in prostate tumors may be important therapeutic agents in at least a subset of patients with metastatic prostate cancer. However, as many of the inhibitors have multiple targets, the efficacy of targeting c-Met alone remains to be determined.

Retrospective analysis of survival outcomes and the role of cisplatin-based chemotherapy in patients with urethral carcinomas referred to medical oncologists

OBJECTIVES Primary carcinomas of the urethra (PCU) are rare and often advanced when diagnosed. Treatment standards are lacking. We studied treatment response and survival in a cohort of patients with PCU, with emphasis on modern platinum-containing chemotherapy regimens plus surgery for advanced disease. MATERIALS AND METHODS This was a retrospective chart review of consecutive patients with PCU seen by medical oncologists at our institution over a recent 5-year period. Outcome was measured as best response to chemotherapy. Kaplan-Meier estimates were generated for survival and Cox proportional hazard was used for prognostic factors for survival. RESULTS The 44 patients (64% women) included had a median age at diagnosis of 66.5 years. The most prevalent histologic subtypes of PCU were squamous cell carcinoma and adenocarcinoma. At diagnosis, 43% already had lymph node-positive [lymph node (LN)+] disease, and 16% had distant metastases. The entire cohorts overall survival (OS) was 31.7 months. The response rate to platinum-containing neoadjuvant chemotherapy was 72%. Twenty-one patients with locally advanced or LN+ PCU underwent chemotherapy plus surgery. Their median OS from chemotherapy initiation was 25.6 months. Four of 9 patients (44%) with LN+ PCU at diagnosis were alive at our review, with a minimum follow-up of more than 3 years. CONCLUSIONS Modern platinum-containing regimens appear to be effective in advanced PCU. Preoperative chemotherapy is associated with prolonged disease-free survival in a subgroup of LN+ cases.

Ligand-independent activation of MET through IGF-1/IGF-1R signaling

The receptor tyrosine kinase, MET, has been implicated in tumorigenesis and metastasis of many solid tumors, by multiple mechanisms, including cross talk with epidermal growth factor receptor. In this study, we examined the role of insulin‐like growth factor receptor‐1 (IGF‐1R) signaling in MET activation, focusing on prostate cancer cells. Stimulation of the prostate cancer cell line PC3 with IGF‐1 induces a delayed phosphorylation of MET at multiple sites (indicative of full activation), reaching a maximum 18 hr after IGF‐1 addition. MET activation does not require the sole MET ligand hepatocyte growth factor (HGF), but does require transcription to occur. Furthermore, direct injection of IGF‐1 is sufficient to induce MET activation in vivo, in a PC3 xenograft model. Pharmacologic or genetic inhibition of the tyrosine kinase, Src, abolishes MET phosphorylation, and expression of activated Src is sufficient to induce Met phosphorylation in the absence of IGF‐1 stimulation. Activated MET is essential for IGF‐1‐mediated increased migration of PC3 cells, demonstrating an important biologic effect of IGF‐1‐mediated MET activation. Finally, we demonstrate that IGF‐1‐induced delayed MET activation occurs in multiple cell lines which express both the receptors, suggesting that IGF‐1R‐mediated MET activation may contribute to tumorigenic properties of multiple cancer types when both growth factor receptors are expressed. The results further suggest that MET may be activated by multiple receptor tyrosine kinase receptors, and dual targeting of these receptors may be important therapeutically.

Combined Inhibition of IGF-1R/IR and Src Family Kinases Enhances Antitumor Effects in Prostate Cancer by Decreasing Activated Survival Pathways

Background Treatment of metastatic prostate cancer (PCa) with single agents has shown only modest efficacy. We hypothesized dual inhibition of different pathways in PCa results in improved tumor inhibition. The Src family kinases (SFK) and insulin-like growth factor-1 (IGF-1) signaling axes are aberrantly activated in both primary PCa and bone metastases and regulate distinct and overlapping functions in PCa progression. We examined the antitumor effects of combined inhibition of these pathways. Materials and Methods Src andIGF-1 receptor (IGF-1R) inhibition was achieved in vitro by short hairpin (sh)RNA and in vitro and in vivo by small molecule inhibitors (dasatinib and BMS-754807, against SFK and IGF-1R/Insulin Receptor(IR), respectively). Results In vitro, inhibition of IGF-1 signaling affected cell survival and proliferation. SFK blockade alone had modest effects on proliferation, but significantly enhanced the IGF-1R blockade. These findings correlated with a robust inhibition of IGF-1-induced Akt1 phophorylation by dasatinib, whereas Akt2 phosphorylation was SFK independent and only inhibited by BMS-754807. Thus, complete inhibition of both Akt genes, not seen by either drug alone, is likely a major mechanism for the decreased survival of PCa cells. Furthermore, dasatinib and BMS-754807 inhibited in vivo growth of the primary human xenograft MDA PCa 133, with corresponding inhibition of Akt in tumors. Also, both orthotopic and intratibial tumor growth of PC-3 cells were more potently inhibited by dual SFK and IGF-1R/IR blockade compared to either pathway alone, with a corresponding decrease in bone turnover markers. Conclusions Dual IGF-1R/IR and SFK inhibition may be a rational therapeutic approach in PCa by blocking both independent and complementary processes critical to tumor growth.

Outcome of therapy‐related acute promyelocytic leukemia with or without arsenic trioxide as a component of frontline therapy

Patients with therapy‐related acute promyelocytic leukemia (t‐APL) have been commonly exposed to topoisomerase inhibitors and may potentially benefit from induction regimens omitting anthracyclines.

Prediction model for mortality after intracranial hemorrhage in patients with leukemia

Intracranial hemorrhage (ICH) is associated with great morbidity and mortality in patients with acute leukemia. We identified 118 patients with ICH from a total of 2,421 patient with leukemia who were treated at our institution between 2005–2009, and assessed the prognostic factors for mortality in the ICH cohort. Median age at time of ICH was 58 years, 49% were male, and 60% had acute myeloid leukemia. The relative incidence of ICH was highest in patients with chronic myeloid leukemia in blast crisis (12.1%). Mental status changes were the most common symptom which prompted work‐up for ICH. Median survival for all patients after onset of ICH was 20 days. In multivariate analyses, four clinical characteristics were identified as independent adverse factors for mortality in patients with ICH: albumin <3.5 g/dL, lactate dehydrogenase (LDH) >835 U/L, age > 60 years, and relapsed disease status. Based on the number of risk factors, mortality after ICH was: 25% (0 risk factor), 47% (1), 78% (2), and >97% (3 or 4). In conclusion, patients with leukemia who develop ICH do not have universally poor outcomes, and a simple scoring system could serve to advise physicians and families of the prognosis and the potential benefit of aggressive treatment options. Am. J. Hematol. 2011.