Immune Activation following Irbesartan Treatment in a Colorectal Cancer Patient: A Case Study.

Colorectal cancers are one of the most prevalent tumour types worldwide and, despite the emergence of targeted and biologic therapies, have among the highest mortality rates. The Personalized OncoGenomics (POG) program at BC Cancer performs whole genome and transcriptome analysis (WGTA) to identify specific alterations in an individual's cancer that may be most effectively targeted. Informed using WGTA, a patient with advanced mismatch repair-deficient colorectal cancer was treated with the antihypertensive drug irbesartan and experienced a profound and durable response. We describe the subsequent relapse of this patient and potential mechanisms of response using WGTA and multiplex immunohistochemistry (m-IHC) profiling of biopsies before and after treatment from the same metastatic site of the L3 spine. We did not observe marked differences in the genomic landscape before and after treatment. Analyses revealed an increase in immune signalling and infiltrating immune cells, particularly CD8+ T cells, in the relapsed tumour. These results indicate that the observed anti-tumour response to irbesartan may have been due to an activated immune response. Determining whether there may be other cancer contexts in which irbesartan may be similarly valuable will require additional studies.

Whole-genome and transcriptome analysis enhances precision cancer treatment options.

BACKGROUND: Recent advances are enabling delivery of precision genomic medicine to cancer clinics. While the majority of approaches profile panels of selected genes or hotspot regions, comprehensive data provided by whole-genome and transcriptome sequencing and analysis (WGTA) present an opportunity to align a much larger proportion of patients to therapies. PATIENTS AND METHODS: Samples from 570 patients with advanced or metastatic cancer of diverse types enrolled in the Personalized OncoGenomics (POG) program underwent WGTA. DNA-based data, including mutations, copy number and mutation signatures, were combined with RNA-based data, including gene expression and fusions, to generate comprehensive WGTA profiles. A multidisciplinary molecular tumour board used WGTA profiles to identify and prioritize clinically actionable alterations and inform therapy. Patient responses to WGTA-informed therapies were collected. RESULTS: Clinically actionable targets were identified for 83% of patients, of which 37% of patients received WGTA-informed treatments. RNA expression data were particularly informative, contributing to 67% of WGTA-informed treatments; 25% of treatments were informed by RNA expression alone. Of a total 248 WGTA-informed treatments, 46% resulted in clinical benefit. RNA expression data were comparable to DNA-based mutation and copy number data in aligning to clinically beneficial treatments. Genome signatures also guided therapeutics including platinum, poly-ADP ribose polymerase inhibitors and immunotherapies. Patients accessed WGTA-informed treatments through clinical trials (19%), off-label use (35%) and as standard therapies (46%) including those which would not otherwise have been the next choice of therapy, demonstrating the utility of genomic information to direct use of chemotherapies as well as targeted therapies. CONCLUSIONS: Integrating RNA expression and genome data illuminated treatment options that resulted in 46% of treated patients experiencing positive clinical benefit, supporting the use of comprehensive WGTA profiling in clinical cancer care.

Successful targeting of the NRG1 pathway indicates novel treatment strategy for metastatic cancer.

BACKGROUND: NRG1 fusion-positive lung cancers have emerged as potentially actionable events in lung cancer, but clinical support is currently limited and no evidence of efficacy of this approach in cancers beyond lung has been shown. PATIENTS AND METHODS: Here, we describe two patients with advanced cancers refractory to standard therapies. Patient 1 had lung adenocarcinoma and patient 2 cholangiocarcinoma. Whole-genome and transcriptome sequencing were carried out for these cases with select findings validated by fluorescence in situ hybridization. RESULTS: Both tumors were found to be positive for NRG1 gene fusions. In patient 1, an SDC4-NRG1 gene fusion was detected, similar gene fusions having been described in lung cancers previously. In patient 2, a novel ATP1B1-NRG1 gene fusion was detected. Cholangiocarcinoma is not a disease type in which NRG1 fusions had been described previously. Integrative genome analysis was used to assess the potential functional significance of the detected genomic events including the gene fusions, prioritizing therapeutic strategies targeting the HER-family of growth factor receptors. Both patients were treated with the pan HER-family kinase inhibitor afatinib and both displayed significant and durable response to treatment. Upon progression sites of disease were sequenced. The lack of obvious genomic events to describe the disease progression indicated that broad transcriptomic or epigenetic mechanisms could be attributed to the lack of prolonged response to afatinib. CONCLUSION: These observations lend further support to the use of pan HER-tyrosine kinase inhibitors for the treatment of NRG1 fusion-positive in both cancers of lung and hepatocellular origin and indicate more broadly that cancers found to be NRG1 fusion-positive may benefit from such a clinical approach regardless of their site of origin. CLINICAL TRIAL INFORMATION: Personalized Oncogenomics (POG) Program of British Columbia: Utilization of Genomic Analysis to Better Understand Tumour Heterogeneity and Evolution (NCT02155621).

Personalized oncogenomics in the management of gastrointestinal carcinomas-early experiences from a pilot study.

BACKGROUND: Gastrointestinal carcinomas are genomically complex cancers that are lethal in the metastatic setting. Whole-genome and transcriptome sequencing allow for the simultaneous characterization of multiple oncogenic pathways. METHODS: We report 3 cases of metastatic gastrointestinal carcinoma in patients enrolled in the Personalized Onco-Genomics program at the BC Cancer Agency. Real-time genomic profiling was combined with clinical expertise to diagnose a carcinoma of unknown primary, to explore treatment response to bevacizumab in a colorectal cancer, and to characterize an appendiceal adenocarcinoma. RESULTS: In the first case, genomic profiling revealed an IDH1 somatic mutation, supporting the diagnosis of cholangiocarcinoma in a malignancy of unknown origin, and further guided therapy by identifying epidermal growth factor receptor amplification. In the second case, a BRAF V600E mutation and wild-type KRAS profile justified the use of targeted therapies to treat a colonic adenocarcinoma. The third case was an appendiceal adenocarcinoma defined by a p53 inactivation; Ras/raf/mek, Akt/mtor, Wnt, and notch pathway activation; and overexpression of ret, erbb2 (her2), erbb3, met, and cell cycle regulators. SUMMARY: We show that whole-genome and transcriptome sequencing can be achieved within clinically effective timelines, yielding clinically useful and actionable information.

Evidence for increased nitric oxide production in the auditory brain stem of the aged dwarf hamster (Phodopus sungorus): an NADPH-diaphorase histochemical study.

Age-related changes of the auditory system such as presbyacusis are believed to be due, at least in part, to alterations of central structures. The superior olivary complex (SOC), a group of interrelated brain stem nuclei, projects to a variety of neuronal structures including the cochlea and the inferior colliculus (IC). The soluble gas nitric oxide (NO), believed to function as a neuroactive substance within the SOC and cochlea, is thought to be involved in ageing processes. Since it is unknown whether NO-production is altered in the ageing auditory system, the present study was conducted to investigate whether the number of NO-producing cells in the SOC is changed with increasing age. The histochemical detection of NADPH-diaphorase activity (NADPH-d), a marker for neurons containing NOS, was utilized to investigate the numbers of NO-producing cells in the SOC of adult and senile Djungarian dwarf hamsters (Phodopus sungorus). Our results demonstrate that the number of stained neurons was almost doubled in the SOC of senile hamsters. The most distinct changes were observed in the medial nucleus of the trapezoid body. In contrast, NO-producing preganglionic sympathetic neurons of the spinal intermediolateral nucleus, which was studied for comparison, did not exhibit significant differences between adult and senile animals. It is concluded that the increase of NO-production in the ageing auditory brain stem, as revealed by our data, may be related to hearing impairments with increasing age.