KRAS mutation is a confirmed predictive biomarker for anti-EGFR monoclonal antibody therapy response for metastatic colorectal cancer. However, its prognosis impact and the predictive potential for first-line standard chemotherapy remains unclear. On the other hand, V600E mutation is the most frequent and studied mutation in the BRAF gene, and it has been associated with a poor outcome of patients and a low response to anti-EGFR treatment. Thus, the aim of this study is to evaluate the role of KRAS and BRAF mutations as prognosis factors and predictive biomarkers for 1st line standard chemotherapy in metastatic colorectal cancer. KRAS mutations and BRAF V600E mutations exhibited a poor outcome (p = 0.021 and p < 0.0001, respectively). Cox multivariate analysis showed that the presence of liver metastasis (HR = 1.595; 95% CI: 1.086–2.343; p = 0.017), KRAS mutation (HR = 1.643; 95% CI: 1.110–2.431; p = 0.013) and BRAF V600E mutation (HR = 5.861; 95% CI: 2.531–13.570; p < 0.0001) were statistically significant co-variables for progression-free survival. Interestingly, patients with KRAS mutations were associated with a poor response to first line standard chemotherapy (p = 0.008). In contrast, the BRAF V600E mutation did not have any impact on the first line standard chemotherapy response (p = 0.540). Therefore, in the present study, we provide new insight on the role of KRAS and BRAF, not only as prognosis biomarkers, but also as first line standard chemotherapy response biomarkers in metastatic colorectal cancer.

MicroRNA-21 expression efficiently predicts preoperative chemoradiotherapy pathological response in locally advanced rectal cancer.

The neurotrophin family of growth factors and their receptors support the survival of several neuronal and non-neuronal cell populations during embryonic development and adult life. Neurotrophins are also involved in malignant transformation. To seek the role of neurotrophin signaling in human lung cancer we studied the expression of neurotrophin receptors in human lung adenocarcinomas and investigated the effect of the neurotrophin receptor inhibitor K252a in A549 cell survival and colony formation ability in soft agar. We showed that human lung adenocarcinomas express TrkA and TrkB, but not TrkC; A549 cells, derived from a human lung adenocarcinoma, express mRNA transcripts encoding nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), TrkA, TrkB, and p75, and high protein levels of TrkA and TrkB. Stimulation of cells using NGF or BDNF activates the anti-apoptotic protein Akt. Interestingly, inhibition of neurotrophin receptor signaling using K252a prevents Akt activation in response to NGF or BDNF, induces apoptotic cell death, and diminishes the ability of A549 cells to growth in soft agar. The data suggest that neurotrophin signaling inhibition using k252a may be a valid therapy to treat patients with lung adenocarcinomas.

Background: PRMT5 regulates proteins important for tumorigenesis via symmetric arginine dimethylation (SDMA). JNJ64619178 is an oral, potent and selective PRMT5 inhibitor that demonstrates efficacy in multiple tumor models. Here, we present a phase I study of JNJ64619178 in adults with advanced solid tumors and non-Hodgkin lymphoma (Part 1).Methods: Dose escalation was supported by a modified continual reassessment method. Patients (pts) received JNJ64619178 either intermittently (14 days on/7 days off) or once daily (QD) on a 21-day cycle. Safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy were evaluated to identify the recommended phase II doses (RP2D).Results: Fifty-four pts were enrolled as of 17 Mar 2020. The most common tumor types were adenoid cystic carcinoma (ACC; 20%), prostate cancer (15%), and uveal melanoma (13%). Median age was 59 (range 28-82), and median number of prior systemic therapies was 3 (range 0-11). Dosing ranged from 0.5 mg to 4 mg intermittently, and from 1 mg to 2 mg QD. Median treatment duration was 1.5 mo (range 0.4-22.4). The only dose-limiting toxicity observed was thrombocytopenia, at 3 and 4 mg intermittently and 2 mg QD. Fifty-one pts (91%) experienced treatment-related adverse events (TRAE), the most common being thrombocytopenia (52%), anemia (41%), nausea (39%), fatigue (32%), dysgeusia (30%), asthenia (24%), and diarrhea (20%). Grade 3/4 TRAEs in >1 pt were thrombocytopenia (20%), anemia (17%), and neutropenia (6%). Thirty pts (56%) had dose interruptions or reductions due to AE. JNJ64619178 plasma C max and AUC were linearly dose-proportional. Robust target engagement, as measured by plasma SDMA, was achieved even with intermittent dosing. A confirmed partial response (RECIST) was observed in ACC, and 7 pts (13%) with ACC, prostate cancer, salivary gland carcinomas, and other tumor types had stable disease >6 mo. Two provisional RP2Ds were selected: 1.5 mg intermittently and 1 mg QD.Conclusions: JNJ64619178 demonstrated manageable toxicity and preliminary evidence of antitumor activity at selected dose levels. Intermittent dosing maintains target inhibition. Assessment of two provisional RP2Ds is ongoing.Clinical trial identification: NCT03573310.

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3095 Background: SRA737 is a potent, highly selective and orally-bioavailable inhibitor of checkpoint kinase 1 (Chk1). SRA737-02 was designed to investigate the safety, tolerability and preliminary activity of SRA737 in a novel combination with sub-therapeutic doses of gemcitabine (low dose gemcitabine; LDG) utilized to potentiate SRA737’s activity by induction of replication stress in subjects with advanced solid tumors. Methods: Phase 1 dose escalation investigated cohorts of 3 to 6 subjects receiving escalating doses of SRA737 for 2 days after LDG administration on days 1, 8, 15 of 28-day cycles. Phase 2 expansion cohorts explored the hypothesis that LDG strongly synergizes with SRA737 in subjects with genetically-defined tumors hypothesized to be sensitive to Chk1 inhibition: urothelial, high grade serous ovarian, small cell lung, soft tissue sarcoma, and cervical or anogenital cancers. Results: A total of 55 subjects received SRA737 in 13 dose escalation cohorts at doses of 40 to 600 mg SRA737 combined with LDG doses of 50 to 300 mg/m2. No protocol-defined dose limiting toxicities (DLTs) have been observed. The pharmacokinetic profile of SRA737 revealed an AUC0-24 and Cmax of 3550 ng∙h/mL and 548 ng/mL at 150 mg SRA737. At this dose, the Cmin (52 ng/mL) exceeded that determined in preclinical models to be effective. Enrollment into expansion cohorts was initiated at 500 mg SRA737 plus 100 mg/m2 LDG with intra-patient dose escalation permitted to 250 mg/m2 LDG. Approximately 80 subjects were planned and 82 have been treated. Median treatment duration was 51 days (range 1 to 358). The most common treatment-emergent adverse events were nausea (53%), vomiting (45%), fatigue (40%), diarrhea (38%), and anemia (28%); the majority were of mild to moderate severity. Proof-of-concept clinical activity has been seen in tumor types such as anal, cervical, and rectal. Conclusions: The combination of LDG and SRA737 has been well tolerated. This first-in-human clinical study provides proof-of-concept that sub-therapeutic LDG effectively potentiates SRA737. This novel replication stress-targeted therapy warrants further evaluation in genetically pre-defined solid tumors. Clinical trial information: NCT02797977.

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