Christel C. Bastida

Effect of the RET Inhibitor Vandetanib in a Patient With RET Fusion–Positive Metastatic Non–Small-Cell Lung Cancer

Introduction Aberrations of RET, the proto-oncogene that encodes rearranged during transfection (RET) transmembrane receptor tyrosine kinase, are associated with the development of several malignancies. Several RET rearrangements, specifically fusions, have been identified in non– small-cell lung cancer (NSCLC), including kinesin family member 5b (KIF5B) –RET, coiled-coil domain-containing protein 6 (CCDC6) –RET, nuclear receptor coactivator 4 (NCOA4) –RET, and tripartite motif-containing 33 (TRIM33) –RET. RET gene fusions occur in approximately 1% to 2% of unselected NSCLCs. RET fusions tend to occur in patients who are younger than age 60 years, former light smokers or never-smokers, with early lymph node metastasis and tumors that are poorly differentiated. RET fusions may be mutually exclusive, with activating mutations in EGFR, HER2, BRAF, and KRAS, as well as EML4-ALK and ROS-1 rearrangements, suggesting that these fusions may be targetable driver mutations. Vandetanib is an orally active small-molecule receptor tyrosine kinase inhibitor that inhibits vascular endothelial growth factor receptor (VEGFR), human epidermal growth factor receptor 2, epidermal growth factor receptor (EGFR), and RET, and is approved by the US Food and Drug Administration for treatment of medullary thyroid carcinoma. Previous trials of vandetanib in patients with NSCLC did not test for or select for RET mutations or fusions, and therefore the clinical efficacy of vandetanib in this subpopulation of NSCLC is currently unknown. Here we describe a patient with NSCLC with a known RET fusion who was treated with the RET inhibitor vandetanib and achieved a dramatic response that has continued for more than 5 months (at the time of submission of this article). Case Report A 36-year-old Asian woman, a never-smoker, with lung adenocarcinoma and RET rearrangement (CCDC6-RET fusion), who was found to have widely metastatic lung cancer, presented with a mass in the right neck and innumerable metastatic nodules in the lung. Computed tomography (CT) of the neck and chest revealed enlarged lymph nodes in the right supraclavicular region, right posterior triangle, and right internal jugular chain, with the largest lymph node measuring 1.5 cm in the right supraclavicular area. Innumerable noncalcified bilateral pulmonary nodules were found, with the largest measuring 1.3 cm in the right upper lobe, and mediastinal lymphadenopathy, including a 1.9-cm pretracheal retrocaval node and a 1.3-cm aortopulmonary window node, was also identified. Excisional biopsy of a right cervical lymph node revealed metastatic, poorly differentiated adenocarcinoma. Immunohistochemical studies showed positive staining for thyroid transcription factor-1 and napsin A and negative staining for thyroglobulin, paired-box gene 8 (PAX8), mammaglobin, and estrogen and progesterone receptors in the malignant cells. Depicted in Figure 1 is a hematoxylin and eosin– stained section showing the histologic appearance of the tumor (Fig 1A), an immunohistochemical preparation showing strong cytoplasmic positivity for napsin A (Fig 1B), and an immunohistochemical preparation demonstrating a lack of expression for thyroglobulin (Fig 1C). The histologic features of the tumor, together with the strong positivity for transcription factor-1 and napsin A and the negative staining for thyroglobulin and PAX8, supported the diagnosis of metastatic lung adenocarcinoma. Treatment with the EGFR tyrosine kinase inhibitor erlotinib was started while awaiting tumor DNA sequencing analysis of EGFR, which later revealed no evidence of an EGFR mutation. Restaging scans after 2 months revealed stable findings. However, because of poor tolerance, the treatment was changed to carboplatin, pemetrexed, and bevacizumab, which resulted in slight initial improvement of the metastases but was discontinued after 9 months because of progressive disease. The patient next received treatment as part of a clinical trial of an anti–interleukin-1 monoclonal

Differential responsiveness to fluoxetine during puberty.

In male golden hamsters (Mesocricetus auratus), attack frequency decreases during puberty. As serotonin inhibits offensive responses in adult hamsters, it is hypothesized that the serotonin system becomes upregulated in the hypothalamus during puberty. This hypothesis was tested through acute treatment with fluoxetine, a serotonin reuptake inhibitor, as well as through analysis of serotonin innervation in specific brain areas. In adults, fluoxetine treatment inhibited aggressive behavior. In juveniles, high doses of fluoxetine only reduced offensive responses (i.e., frequency and repetition of attacks), whereas low doses enhanced them. Juveniles also showed a dose-specific maturation of attack targets. In addition, the density of serotonin innervation of the hypothalamus was 20% higher in adult hamsters compared with juveniles. On the basis of these data, it is proposed that the developing serotonergic system shapes the development of offensive behaviors in male golden hamsters.

Functional networks underlying latent inhibition learning in the mouse brain

The present study reports the first comprehensive map of brain networks underlying latent inhibition learning and the first application of structural equation modeling to cytochrome oxidase data. In latent inhibition, repeated exposure to a stimulus results in a latent form of learning that inhibits subsequent associations with that stimulus. As neuronal energy demands to form learned associations changes, so does the induction of the respiratory enzyme cytochrome oxidase. Therefore, cytochrome oxidase can be used as an endpoint metabolic marker of the effects of experience on regional brain metabolic capacity. Quantitative cytochrome oxidase histochemistry was used to map brain regions in mice trained on a tone-footshock fear conditioning paradigm with either tone preexposure (latent inhibition), conditioning only (acquisition), conditioning followed by tone alone (extinction), or no handling or conditioning (naive). The ventral cochlear nucleus, medial geniculate, CA1 hippocampus, and perirhinal cortex showed modified metabolic capacity due to latent inhibition. Structural equation modeling was used to determine the causal influences in an anatomical network of these regions and others thought to mediate latent inhibition, including the accumbens and entorhinal cortex. An uncoupling of ascending influences between auditory regions was observed in latent inhibition. There was also a reduced influence on the accumbens from the perirhinal cortex in both latent inhibition and extinction. The results suggest a specific network with a neural mechanism of latent inhibition that appears to involve sensory gating, as evidenced by modifications in metabolic capacity and effective connectivity between auditory regions and reduced perirhinal cortex influence on the accumbens.

Aurora Kinase Inhibitors in Oncology Clinical Trials: Current State of the Progress

The Aurora kinase family of kinases (Aurora A, B, and C) are involved in multiple mitotic events, and aberrant expression of these kinases is associated with tumorigenesis. Aurora A and Aurora B are validated anticancer targets, and the development of Aurora kinase inhibitors has progressed from preclinical to clinical studies. A variety of Aurora A, B and pan-Aurora kinase inhibitors have entered the clinic. The main side effects include febrile neutropenia, stomatitis, gastrointestinal toxicity, hypertension, and fatigue. Responses including complete remissions have been described in diverse, advanced malignancies, most notably ovarian cancer and acute myelogenous leukemia. This review highlights the biologic rationale for Aurora kinase as a target, and clinical trials involving Aurora kinase inhibitors, with particular emphasis on published early phase studies, and the observed anti-tumor activity of these agents.

Contrasting hippocampal and amygdalar expression of genes related to neural plasticity during escape from social aggression.

Social subjugation has widespread consequences affecting behavior and underlying neural systems. We hypothesized that individual differences in stress responsiveness were associated with differential expression of neurotrophin associated genes within the hippocampus and amygdala. To do this we examined the brains of hamsters placed in resident/intruder interactions, modified by the opportunity to escape from aggression. In the amygdala, aggressive social interaction stimulated increased BDNF receptor TrK(B) mRNA levels regardless of the ability to escape the aggressor. In contrast, the availability of escape limited the elevation of GluR(1) AMPA subunit mRNA. In the hippocampal CA(1), the glucocorticoid stress hormone, cortisol, was negatively correlated with BDNF and TrK(B) gene expression, but showed a positive correlation with BDNF expression in the DG. Latency to escape the aggressor was also negatively correlated with CA(1) BDNF expression. In contrast, the relationship between amygdalar TrK(B) and GluR(1) was positive with respect to escape latency. These results suggest that an interplay of stress and neurotrophic systems influences learned escape behavior. Animals which escape faster seem to have a more robust neurotrophic profile in the hippocampus, with the opposite of this pattern in the amygdala. We propose that changes in the equilibrium of hippocampal and amygdalar learning result in differing behavioral stress coping choices.

Human epidermal receptor 2-amplified salivary duct carcinoma: regression with dual human epidermal receptor 2 inhibition and anti-vascular endothelial growth factor combination treatment.

Salivary ductal carcinoma is a rare cancer with poor prognosis and limited treatment options. Human epidermal receptor 2 (HER2)‐directed treatment has been attempted in HER2‐amplified or overexpressed salivary gland malignancies with limited success.

Non-small-cell lung cancer with HER2 exon 20 mutation: regression with dual HER2 inhibition and anti-VEGF combination treatment.

Advances in cancer genome sequencing technologies have led to the identification of non-small cell lung cancer (NSCLC) subtypes having distinct potentially actionable molecular drivers, including mutations in the kinase domain of human epidermal growth factor receptor-2 (HER2) which have been reported in approximately 4% of NSCLC cases.1 Preclinical and clinical studies demonstrated that HER2 mutations in NSCLC are associated with a favorable response to HER2 targeted therapies.2, 3

Dual HER2 inhibition in combination with anti-VEGF treatment is active in heavily pretreated HER2-positive breast cancer

BACKGROUND Preclinical data indicate that dual HER2 inhibition overcomes trastuzumab resistance and that use of an HER2 inhibitor with an anti-angiogenic agent may augment responses. PATIENTS AND METHODS We conducted a dose-escalation, phase I study of a combination of trastuzumab, lapatinib and bevacizumab. The subset of patients with metastatic breast cancer was analyzed for safety and response. RESULTS Twenty-six patients with metastatic breast cancer (median = 7 prior systemic therapies) (all with prior trastuzumab; 23 with prior lapatinib; one with prior bevacizumab) received treatment on a range of dose levels. The most common treatment-related grade 2 or higher toxicities were diarrhea (n = 11, 42%) and skin rash (n = 2, 8%). The recommended phase 2 dose was determined to be the full Food and Drug Administration (FDA) approved doses for all the three agents (trastuzumab 8 mg/kg loading dose, 6 mg/kg maintenance dose, intravenously every 3 weeks; lapatinib 1250 mg daily, bevacizumab 15 mg/kg intravenously every 3 weeks). The overall rate of stable disease (SD) ≥6 months and partial or complete remission (PR/CR) was 50% (five patients with SD ≥6 months; seven PRs (including one unconfirmed); one CR). The rate of SD ≥6 months/PR/CR was not compromised in patients who had previously received study drugs, those with brain metastases, and patients treated at lower dose levels. CONCLUSIONS The combination of trastuzumab, lapatinib and bevacizumab was well-tolerated at maximally approved doses of each drug, and its activity in heavily pretreated patients with metastatic breast cancer suggests that it warrants further investigation. CLINTRIALSGOV ID NCT00543504.

Risk assessment and avoidance in juvenile golden hamsters exposed to repeated stress.

Juvenile hamsters are typically less vulnerable to social subjugation than adults, although they will avoid aggressive individuals in some situations. The purpose of this study was to determine the extent to which social subjugation stimulates fear- or anxiety-like behavior in juvenile hamsters in both social and non-social contexts. Social context testing was conducted in a Y-maze while the non-social context apparatus consisted of an open field arena and a lat-maze. In the Y-maze, subjects were exposed to an unfamiliar aggressive adult hamster. Compared with non-subjugated controls, subjugated juveniles spent significantly more time in the area furthest from the aggressive adult stimulus. In addition, socially stressed animals were more likely to avoid the arm of the maze containing the social stimulus. When they did walk in the arm containing the social stimulus, subjugated individuals were more likely to ambulate slowly. Subjugated hamsters also performed fewer olfactory investigations in the proximity of the unfamiliar aggressive individual. Despite these behavioral differences detected between groups during testing in a social context, we observed no differences between groups in the open field and lat-maze. This suggests that the effects of subjugation observed in the Y-maze are specific to exposure to a social context and that social subjugation in juvenile hamsters does not result in a generalized state of fear. Instead, subjugated juveniles learned to avoid adult males and were otherwise behaviorally similar to non-subjugated controls.

Chronic social stress in puberty alters appetitive male sexual behavior and neural metabolic activity.

Repeated social subjugation in early puberty lowers testosterone levels. We used hamsters to investigate the effects of social subjugation on male sexual behavior and metabolic activity within neural systems controlling social and motivational behaviors. Subjugated animals were exposed daily to aggressive adult males in early puberty for postnatal days 28 to 42, while control animals were placed in empty clean cages. On postnatal day 45, they were tested for male sexual behavior in the presence of receptive female. Alternatively, they were tested for mate choice after placement at the base of a Y-maze containing a sexually receptive female in one tip of the maze and an ovariectomized one on the other. Social subjugation did not affect the capacity to mate with receptive females. Although control animals were fast to approach females and preferred ovariectomized individuals, subjugated animals stayed away from them and showed no preference. Cytochrome oxidase activity was reduced within the preoptic area and ventral tegmental area in subjugated hamsters. In addition, the correlation of metabolic activity of these areas with the bed nucleus of the stria terminalis and anterior parietal cortex changed significantly from positive in controls to negative in subjugated animals. These data show that at mid-puberty, while male hamsters are capable of mating, their appetitive sexual behavior is not fully mature and this aspect of male sexual behavior is responsive to social subjugation. Furthermore, metabolic activity and coordination of activity in brain areas related to sexual behavior and motivation were altered by social subjugation.