Benny Johnson

Reciprocal feedback inhibition of the androgen receptor and PI3K as a novel therapy for castrate-sensitive and -resistant prostate cancer

Gain-of-function of the androgen receptor (AR) and activation of PI3K/AKT/mTOR pathway have been demonstrated to correlate with progression to castration-resistant prostate cancer (CRPC). However, inhibition of AR or PI3K/mTOR alone results in a reciprocal feedback activation. Therefore, we hypothesized that dual inhibition of the AR and PI3K/mTOR pathway might lead to a synergistic inhibition of cell growth and overcome drug resistance in CRPC. Here, we reported that androgen-depletion increased AR protein level and Akt phosphorylation at Ser473 and Thr308 in LNCaP cells. Moreover, we developed resistance cell lines of LNCaP to Enzalutamide (or MDV3100), an AR inhibitor (named as LNCaP ‘MDV-R’) and PF-04691502, a PI3K/mTOR inhibitor (named as LNCaP ‘PF-R’). MTS analysis showed that LNCaP ‘PF-R’ was strongly resistant to Enzalutamide treatment, and on the other hand, LNCaP ‘MDV-R’ was 6-fold resistant to PF-04691502 treatment. Mechanistically, LNCaP ‘MDV-R’ cells had significantly reduced AR, loss of PSA and increase Akt activity in contrast with LNCaP ‘PF-R’ cells. Combined inhibition of PI3K/mTOR and AR pathways with a variety of small molecular inhibitors led to a synergistic suppression of cell proliferation and a profound increase of apoptosis and cell cycle arrest in both androgen-dependent LNCaP and independent CRPC 22Rv1 cell lines. In conclusion, this study provides preclinical proof-of-concept that the combination of a PI3K/mTOR inhibitor with an AR inhibitor results in a synergistic anti-tumor response in non-CRPC and CRPC models.

Secondary acute lymphoblastic leukemia is an independent predictor of poor prognosis

Compared to secondary acute myeloid leukemia, secondary acute lymphoblastic leukemia (sALL) is poorly characterized. We utilized data from the Surveillance, Epidemiology, and End Results (SEER) 13 database to further elucidate patient characteristics and prognostic factors in sALL. Cases of adult de novo acute lymphoblastic leukemia (ALL) and sALL in patients with primary breast, rectum, cervix, or ovarian cancers or lymphoma with a latency period of at least 12 months were identified within the SEER 13 database. Survival in sALL and de novo ALL were compared after propensity matching based on age, gender, race, ALL subtype, and year of diagnosis. 4124 cases of de novo ALL and 79 cases of sALL were identified. sALL patients were older at diagnosis (median 62 years vs. 44 years; p<0.01). Overall survival (OS) in sALL was lower than de novo ALL (median 8 months vs. 11 months), 1 year OS: 35% vs. 47% (p=0.05), 2 year OS: 16% vs. 31% (p<0.01), and 5 year OS: 7% vs. 21% (p<0.01). Multivariate analysis revealed sALL as an independent predictor of worsened survival (adjusted HR 1.54; 95% CI 1.16-2.04, p<0.01) after propensity matching.

Comorbidities Drive Outcomes for Both Malignancy-Associated and Non–Malignancy-Associated Hemophagocytic Syndrome

BACKGROUNDnSecondary hemophagocytic syndrome (SHPS) is a syndrome that develops as a result of infection, autoimmunity, or underlying malignancy. We studied novel predictors of mortality among adults with SHPS.nnnPATIENTS AND METHODSnSHPS were identified from the Nationwide Inpatient Sample for 2009 to 2011 using International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM), codes. Charlson comorbidity index (CCI) was used for comorbidity assessment, excluding malignancy. Patient- and hospital-related factors on mortality were assessed by chi-square test or analysis of variance. P values were 2 sided, and the level of significance was .05.nnnRESULTSnA total of 276 patient hospitalizations with SHPS were identified. Forty-four had an associated malignancy, 38 (86%) of which were hematologic. Median age was 42 years (range, 18-89 years). A total of 66% (n = 182) had a CCI of 0, 13% (n = 27) had a CCI of 1, and 21% (n = 57) had a CCI of 2 or more. On bivariate analysis, inpatient mortality rate was significantly higher in malignancy-associated hemophagocytic syndrome (HPS) (odds ratio [OR], 2.07; P = .04), age ≥ 50 years (OR, 3.46; P < .01), CCI ≥ 2 (OR, 3.04; P < .01), and Medicare patients (OR, 2.32; P < .01). In multivariate analysis, CCI ≥ 2 remained an independent predictor of survival in the overall study cohort (OR, 3.52; 95% confidence interval, 1.51-8.18; P < .01).nnnCONCLUSIONnMalignancy-associated HPS, CCI ≥ 2, age > 50 years, and Medicare patients were associated with a worse in-hospital mortality. In multivariate analysis, greater comorbidity burden appeared to be the single most important predictor of mortality. This suggests that outcomes for adults with HPS are predicated by the extent of organ dysfunction at diagnosis.

Next generation sequencing identifies ‘interactome’ signatures in relapsed and refractory metastatic colorectal cancer

BACKGROUNDnIn the management of metastatic colorectal cancer (mCRC), KRAS, NRAS and BRAF mutational status individualizes therapeutic options and identify a cohort of patients (pts) with an aggressive clinical course. We hypothesized that relapsed and refractory mCRC pts develop unique mutational signatures that may guide therapy, predict for a response and highlight key signaling pathways important for clinical decision making.nnnMETHODSnRelapsed and refractory mCRC pts (N=32) were molecularly profiled utilizing commercially available next generation sequencing (NGS) platforms. Web-based bioinformatics tools (Reactome/Enrichr) were utilized to elucidate mutational profile linked pathways-networks that have the potential to guide therapy.nnnRESULTSnPts had progressed on fluoropyrimidines, oxaliplatin, irinotecan, bevacizumab, cetuximab and/or panitumumab. Most common histology was adenocarcinoma (colon N=29; rectal N=3). Of the mutations TP53 was the most common, followed by APC, KRAS, PIK3CA, BRAF, SMAD4, SPTA1, FAT1, PDGFRA, ATM, ROS1, ALK, CDKN2A, FBXW7, TGFBR2, NOTCH1 and HER3. Pts had on average had ≥5 unique mutations. The most frequent activated signaling pathways were: HER2, fibroblast growth factor receptor (FGFR), p38 through BRAF-MEK cascade via RIT and RIN, ARMS-mediated activation of MAPK cascade, and VEGFR2.nnnCONCLUSIONSnDominant driver oncogene mutations do not always equate to oncogenic dependence, hence understanding pathogenic interactome(s) in individual pts is key to both clinically relevant targets and in choosing the next best therapy. Mutational signatures derived from corresponding pathway-networks represent a meaningful tool to (I) evaluate functional investigation in the laboratory; (II) predict response to drug therapy; and (III) guide rational drug combinations in relapsed and refractory mCRC pts.

Under-recognition of hemophagocytic syndrome in United States' rural, non-teaching hospitals.

Hemophagocytic syndrome (HPS) is a rare clinical syndrome characterized by hyper-inflammation due to an excessive immune response with an aggressive disease course and life-threatening consequences. Familial HPS is an autosomal recessive disorder caused by various gene defects that usually presents in infants and children.[1–4] Acquired or secondary HPS (SHPS) can occur at any age but primarily arises in adults due to extreme immunologic activation, which can be triggered, by infections, autoimmune disorders, and malignancies, with leukemia and lymphoma being the most common.[5,6] This syndrome is highly fatal without prompt diagnosis and treatment, but its rarity and complex clinical picture often leads to a delayed or missed diagnosis. Epidemiologic data on SHPS in the adult population is sparse. We sought to define the characteristics of SHPS in different hospital settings as well as the mortality when associated with hematologic malignancies, solid tumors, and in patients without a reported malignancy. We obtained IRB approval to search the United States Nationwide Inpatient Sample (NIS) database for adult patients diagnosed with HPS.[7] Utilizing search parameters established by Johnson et al. [8], we identified all adult hospitalizations from 2009 to 2011 with the diagnosis of HPS based on International Classification of Diseases-9th revision, Clinical Modification (ICD-9-CM) code 288.4 combined with ICD-9-CM procedure code 41.31 for bone marrow biopsy to improve diagnostic accuracy. Patient characteristics included age at diagnosis, race, and gender. We identified the underlying conditions associated with each case (malignant vs non-malignant) as well as the inpatient mortality. Lastly, we assessed the distribution of cases by hospital teaching status (teaching versus non-teaching) and location (rural versus urban). Statistical analysis was done using STATA 13.0 (StataCorp LP, College Station, TX). All p values were two sided and the level of significance was 0.05. A total of 896 HPS cases were identified and 276 of those cases also had bone marrow biopsies. Of the 276 cases identified for analysis, 44 (16%) had a concomitant diagnosis of a malignancy. The median age at diagnosis was 42 years (range 18–89 years), and 43% (n1⁄4 114) of the cases were females. Of the 232 non-malignant HPS cases, related causes could only be identified for 37 patients: 1 HIV (1%), 3 histoplasmosis (1%), 12 systemic lupus erythematosus (4%), and 21 rheumatoid arthritis (7%). There were a total of 23,634,793 hospitalizations in the NIS from 2009 to 2011; 12,532,948 (53%) belonged to non-teaching hospitals and 11,101,845 (47%) belonged to teaching hospitals. Similarly, 2,867,148 (12%) belonged to rural hospitals and 20,767,645 (88%) belonged to urban hospitals. Among HPS cases, 90% (n1⁄4 248) belonged to teaching hospitals and 99% (n1⁄4 273) belonged to urban hospitals. Chi-squared test showed that cases of HPS were more likely to be diagnosed in a teaching hospital (p < 0.01) and urban hospitals (p< 0.01). Of the 44 cases with an underlying malignancy, 38 (86%) were associated with a hematological malignancy and 5 (11.3%) with a solid tumor. The tumor type was not specified for one patient. The in-hospital mortality for HPS with and without underlying malignancy was 29.6% (n1⁄4 13) and 14.2% (n1⁄4 33), respectively (p value 0.01) [Table 1]. Inpatient mortality was 29% (n1⁄4 11) for patients with an associated hematological malignancy and 40% (n1⁄4 2) for those with associated solid tumor. Comparison of outcomes between rural and urban hospitals and teaching and non-teaching hospitals was not feasible due to the skewing of case distributions. To better understand reasons for the concentration of HPS cases in urban centers, we explored referral patterns using the NIS ‘‘transfer out’’ variable, which was only available in 2010 and 2011. Data was available for two of the three cases diagnosed in rural hospitals, and neither case

Emerging Role and Targeting of Carcinoembryonic Antigen-related Cell Adhesion Molecule 6 (CEACAM6) in Human Malignancies

Background: Carcinoembryonic antigen-related cell adhesion molecule 6 (CEACAM6) is a member of the CEA family of cell adhesion proteins that belong to the immunoglobulin superfamily. CEACAM6 is normally expressed on the surface of myeloid (CD66c) and epithelial surfaces. Stiochiomertic expression of members of the CEA family (CEACAM1, 5, 6, 7) on epithelia maintains normal tissue architecture through homo-and hetero-philic interactions. Dysregulated over-expression of CEACAM6 is oncogenic, is associated with anoikis resistance and an invasive phenotype mediated by excessive TGFβ, AKT, FAK and SRC signaling in human malignancies. Methods: Extensive literature review through PubMed was conducted to identify relevant preclinical and clinical research publications regarding CEACAM6 over the last decade and was summarized in this manuscript. Results: CEACAM5 and 6 are over-expressed in nearly 70% of epithelial malignancies including colorectal cancer (CRC), pancreatic ductal adenocarcinoma (PDA), hepatobiliary, gastric, breast, non-small cell lung and head/neck cancers. Importantly, CEACAM6 is a poor prognostic marker in CRC, while its expression correlates with tumor stage, metastasis and post-operative survival in PDA. CEACAM6 appears to be an immune checkpoint suppressor in hematologic malignancies including acute lymphoblastic leukemia and multiple myeloma. Several therapeutic monoclonal antibodies or antibody fragments targeting CEACAM6 have been designed and developed as a targeted therapy for human malignancies. A Llama antibody targeting CEACAM6 is being evaluated in early phase clinical trials. Conclusion: This review focuses on the role of CEACAM6 in the pathogenesis and signaling of the malignant phenotype in solid and hematologic malignancies and highlights its potential as a therapeutic target for anti-cancer therapy.

Molecular profiling of a case of advanced pancreatic cancer identifies an active and tolerable combination of targeted therapy with backbone chemotherapy

Typical survival with common 1(st)-line regimens for pancreatic cancer range from 6-11 months. We report a case of a patient with stage IVB pancreatic adenocarcinoma treated with gemcitabine and erlotinib who stopped therapy after 3 months without achieving a response due to intolerance. To decide upon additional treatment options, molecular analysis was performed on liver metastasis which revealed KRAS, FBXW7, APC, and ATM mutations, with thymidylate synthase (TS) negativity and PD-1 positivity. Based on this profile of TS negativity and ATM mutation, a combination strategy was devised consisting of capecitabine, oxaliplatin, bevacizumab and vorinostat. The patient had a near complete response to therapy with this regimen. In refractory metastatic pancreatic cancer, responses of this magnitude are rarely seen. To our knowledge, this represents the first demonstrated activity of this combination in the metastatic setting which could prompt further investigation of its use in large scale clinical trials.

KOC (K homology domain containing protein overexpressed in cancer) overexpression and progression-free survival after curative intent resection of pancreatic ductal adenocarcinoma.

48 Background: Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer mortality in the United States. Unfortunately, effective screening and early detection mechanisms are currently unavailable, thereby 80% of patients present with distant metastasis. Of the subset of patients eligible for curative intent surgery, the 5-year survival rate is only 20%. Negative surgical margins, tumor size, stage, and node negative disease are traditional prognostic indicators. However, these can be limited in their ability to predict patient specific prognosis. KOC is an oncofetal RNA-binding protein involved in RNA stabilization and cell growth during embryogenesis. Previous studies have revealed that KOC mRNA is inappropriately overexpressed in pancreatic cancer and that increased expression correlates with tumor stage. In this study, we attempt to identify whether KOC expression in patients who undergo curative intent surgery correlates with progression free survival.nnnMETHODSnTissue microarrays prepared from formalin-fixed, paraffin-embedded specimens of patients with PDAC who underwent curative intent surgery were assessed by immunohistochemistry.nnnRESULTSnA total of 35 patients were included. Comparisons between groups on progression free survival are estimated using the Kaplan-Meier method and the log-rank test. KOC was overexpressed in 23.6% of tumors. It was found that there were zero patients with a high KOC expression and no distant metastasis. Patients with a high KOC expression were more than 3 times more likely to progress compared to those with a low KOC expression (HR=3.54, 95% CI: 1.34, 9.36, p=0.011).nnnCONCLUSIONSnKOC is a useful prognostic biomarker for predicting those patients with PDAC who have a high risk for early progression and distant metastasis. Identifying patients with high KOC expression upon initial diagnosis can serve as a way to risk stratify patients to aggressive treatment regimens upfront and early exposure to clinical trials.