Peter Croucher | University of California, Berkeley (original) (raw)

Papers by Peter Croucher

Journal of Clinical Oncology, 2022

TPS219 Background: Metastatic CRPC is a leading cause of cancer death worldwide. Although abirate... more TPS219 Background: Metastatic CRPC is a leading cause of cancer death worldwide. Although abiraterone (abi) + prednisone in either castration-sensitive or castration-resistant disease increases survival, resistance is universal and generally occurs within 9-16 months of initiating treatment. Polo-like kinase 1 (PLK1) is a serine/threonine protein kinase that regulates mitotic function and is upregulated in prostate cancer following androgen-deprivation therapy (ADT). Onvansertib is an oral and highly-selective PLK1 inhibitor that demonstrated safety and tolerability as a single agent in a Ph1 trial. Preclinical studies showed that PLK1 inhibition enhanced abi anti-tumor effect in cell line models and in patient-derived tumor xenografts via an AR-independent mechanism. Transcriptomic analyses revealed that abi induced mitosis-related gene sets in cells synergistic for abi + onvansertib, and identified an abi-onvansertib synergy gene signature. Methods: The goal of this phase 2 study ...

Experimental and Molecular Therapeutics, 2018

First generation FLT3 inhibitors have been useful in treating AML (sorafenib, midostaurin). Secon... more First generation FLT3 inhibitors have been useful in treating AML (sorafenib, midostaurin). Second generation inhibitors with more selectivity are currently in P3 trials in AML (quizartinib, gilteritinib). Despite the advances, resistance to FLT3 inhibitors and disease progression while on FLT3 inhibitors remains an important problem for patient care. We analyzed the activity of a highly-selective PLK1 inhibitor, PCM-075 (formerly NMS-1286937), in models of acute myeloid leukemia (AML) alone and in combination with various chemotherapies and targeted therapeutics including FLT3 inhibitors. PCM-075 is a potent, highly-selective adenosine triphosphate competitive inhibitor of PLK1, a serine/threonine kinase, which is over-expressed in hematologic malignancies and solid tumors such as AML, breast, prostate, ovarian, lung, gastric and colon. PCM-075 is highly active in blocking proliferation and inducing G2/M arrest in multiple AML cell lines. In a therapeutic model, PCM-075 was capable of inducing significant tumor growth inhibition (TGI)1, and increasing survival in an in vivo disseminated leukemia model (AML-NS8 Cells)2. Orally administered PCM-075 is currently in development for multiple tumor types and is in clinical trials for the treatment of AML (NCT03303339). Synergistic interactions between Quizartinib, other FLT3 inhibitors and PCM-075 were examined in cell culture models. In vivo, combination studies in an AML FLT3 mutant 21 day treatment xenograft model (MV4-11) revealed synergistic interactions between Quizartinib and PCM-075. PCM-075 (dosed orally 30 mg/kg, QD for days 1-10 and 12 -21) in combination with Quizartinib (1 mg/kg, QD for 21 days) resulted in 97.3% (96.2-98.4) TGI, compared to 77.9% (70.0-85.8) with Quizartinib and 80.2% (70.4-90.0) with PCM-075 as monotherapy. Body weight in treated mice remained within 20% of controls. To better understand the mechanism of the synergistic activity of PCM-075, we have conducted in vitro RNA-based profiling studies examining the combination of PCM-075 with FLT3 inhibitors for impact on specific gene pathways in AML cell lines and this will be presented. Combination therapy is the mainstay of current oncology treatment regimens and these results suggest that combining PCM-075 with FLT3 inhibitors could be useful in the treatment of AML and a potential next step for patients developing resistance to FLT3 inhibitors. 1 Mol Cancer Ther. 2012 Apr;11(4):1006-162 PLoS One. 2013;8(3):e58424 Citation Format: Karena Kosco, Maya Ridinger, Penn Whitley, Peter Croucher, Jeffrey N. Miner, Mark Erlander. Selective Polo-like Kinase 1 (PLK1) inhibitor PCM-075 is highly active alone and shows synergy when combined with FLT3 inhibitors in models of acute myeloid leukemia (AML) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1885.

Biological Journal of the Linnean Society, 2014

Key to our understanding of the mechanisms underlying the process of speciation is the determinat... more Key to our understanding of the mechanisms underlying the process of speciation is the determination of the nature of the barriers to gene flow between related taxa. Species that show zero gene flow in sympatry or parapatry are of little use in this respect. In the present study, we used two closely-related species of large house spider, Tegenaria saeva and Tegenaria gigantea, which hybridize to a limited extent along a natural contact zone in southern Britain. The species are apparently indistinguishable with respect to habitat utilization and phenology. Laboratory crosses using individuals from both allopatric and parapatric populations suggest that, although male and female courtship, as well as web and cuticular-borne pheromones, are conserved between the species, mechanical difficulties are experienced during interspecific copulation. Copulation bouts are, on average, significantly shorter during interspecific matings because of these difficulties, and are probably not sufficiently long for effective sperm transfer to take place. In the two cases of successful interspecific crossing, and in subsequent F1 and backcross generations, there are few indications of differential fertility, fecundity or viability, suggesting little post-zygotic incompatibility. The high success rate of crosses between F1 hybrids and both parental species underlines the principally mechanical barrier to gene flow between these taxa. Once this is breached, there appears to be little impediment to continuing introgression, which could, in some geographical areas at least, ultimately lead to the fusion of the two species. © 2014 The Linnean Society of London, Biological Journal of the Linnean Society, 2014, 113, 355–367.

Journal of Thoracic Oncology, 2016

Lancet, 2001

Genetic predisposition to inflammatory bowel disease (IBD) has been shown by epidemiological and ... more Genetic predisposition to inflammatory bowel disease (IBD) has been shown by epidemiological and linkage studies. Genetic linkage of IBD to chromosome 16 has been previously observed and replicated in independent populations. The recently identified NOD2 gene is a good positional and functional candidate gene since it is located in the region of linkage on chromosome 16q12, and activates nuclear factor (NF) κB in response to bacterial lipopolysaccharides.We sequenced the coding region of the NOD2 gene and genotyped an insertion polymorphism affecting the leucine-rich region of the protein product in 512 individuals with IBD from 309 German or British families, 369 German trios (ie, German patients with sporadic IBD and their unaffected parents), and 272 normal controls. We then tested for association with Crohn's disease and ulcerative colitis.Family-based association analyses were consistently positive in 95 British and 99 German affected sibling pairs with Crohn's disease (combined p<0·0001); the association was confirmed in the 304 German trios with Crohn's disease. No association was seen in the 115 sibling pairs and 65 trios with ulcerative colitis. The genotype-specific disease risks conferred by heterozygous and homozygous mutant genotypes were 2·6 (95% CI 1·5–4·5) and 42·1 (4·3−∞), respectively.The insertion mutation in the NOD2 gene confers a substantially increased susceptibility to Crohn's disease but not to ulcerative colitis.

Twin research and human genetics : the official journal of the International Society for Twin Studies, 2005

Commentary on Cherkas et al. (2004). Genetic Influences on Female Infidelity and Number of Sexual... more Commentary on Cherkas et al. (2004). Genetic Influences on Female Infidelity and Number of Sexual Partners in Humans: A Linkage and Association Study on the Role of the Vasopressin Receptor Gene (AVPR1A).Twin Research, 7, 649–658.

BMC bioinformatics, Jan 23, 2005

Normalization is the process of removing non-biological sources of variation between array experi... more Normalization is the process of removing non-biological sources of variation between array experiments. Recent investigations of data in gene expression databases for varying organisms and tissues have shown that the majority of expressed genes exhibit a power-law distribution with an exponent close to -1 (i.e. obey Zipf's law). Based on the observation that our single channel and two channel microarray data sets also followed a power-law distribution, we were motivated to develop a normalization method based on this law, and examine how it compares with existing published techniques. A computationally simple and intuitively appealing technique based on this observation is presented. Using pairwise comparisons using MA plots (log ratio vs. log intensity), we compared this novel method to previously published normalization techniques, namely global normalization to the mean, the quantile method, and a variation on the loess normalization method designed specifically for boutique ...

Evolution; international journal of organic evolution, 2015

Particularly intriguing examples of adaptive radiation are those in which lineages show parallel ... more Particularly intriguing examples of adaptive radiation are those in which lineages show parallel or convergent evolution, suggesting utilization of similar genetic or developmental pathways. The current study focuses on an adaptive radiation of Hawaiian "spiny-leg" spiders in which diversification is associated with repeated convergent evolution leading to similar sets of ecomorphs on each island. However, two species on the oldest islands in the archipelago exhibit variability, occurring as two different ecomorphs. More derived species on the younger islands show much less variability, any one species displaying a single ecomorph. We measured ecomorphological features within individuals over time to determine the nature of the variability. Then, using transcriptomes, we conducted lineage-based tests for selection under varying models and analyses of gene tree versus species tree incongruencies. Our results provide strong evidence that variability in color in Tetragnatha k...

Public Health Genomics, 2006

Proceedings of the National Academy of Sciences, 2005

Human longevity is a multifactorial condition with a significant genetic contribution. A recent a... more Human longevity is a multifactorial condition with a significant genetic contribution. A recent association study in two independent samples of long-lived U.S. Caucasians [long-lived individuals (LLI)] identified a SNP haplotype of the microsomal triglyceride transfer protein ( MTP , 4q25) that was underrepresented among LLI when compared with younger controls. This suggested that variation in the MTP gene might modify human longevity. Because of its function in lipid metabolism, the MTP gene product could plausibly play a pivotal role in the physiology of aging. However, the association observed in the U.S. samples could not be replicated by the same authors in a larger French LLI sample. We have therefore investigated the MTP “risk” haplotype in our own collection of 1,589 German nonagenarians, centenarians, and appropriately matched controls. No statistically significant differences were observed between LLI and controls at the allele, genotype, or haplotype level. This indicates...

Proceedings of the National Academy of Sciences, 2001

Heritable predisposition to inflammatory bowel disease (IBD) has been demonstrated by epidemiolog... more Heritable predisposition to inflammatory bowel disease (IBD) has been demonstrated by epidemiological and genetic analysis. Linkage of IBD to broad regions of chromosome 16 has been established by analysis of multiple populations. NOD2 , located on proximal 16q, was recently identified as an IBD gene. As the linkage regions on chromosome 16 are large, we have investigated the possibility that NOD2 is not the only IBD gene located on this chromosome. A high-density experiment using 39 microsatellite markers was performed to identify additional regions of association, and to indicate areas of interest for further investigation. A triple-peaked configuration of the linkage curve with peak logarithm of odds (lod) scores of 2.7, 3.2, and 3.1 was observed on proximal 16p, proximal 16q, and central 16q, respectively. The cohort was stratified by coding individuals carrying the NOD2 single nucleotide polymorphism (SNP)8 and SNP13 “unknown.” Significance at the central peak, corresponding to...

Molecular Ecology, 2010

Genetically controlled colour polymorphisms provide a physical manifestation of the operation of ... more Genetically controlled colour polymorphisms provide a physical manifestation of the operation of selection and how this can vary according to the spatial or temporal arrangement of phenotypes, or their frequency in a population. Here, we examine the role of selection in shaping the exuberant colour polymorphism exhibited by the spider Theridion californicum. This species is part of a system in which several distantly related spiders in the same lineage, but living in very different geographical areas, exhibit remarkably convergent polymorphisms. These polymorphisms are characterized by allelic inheritance and the presence of a single common cryptic morph and, in the case of T. californicum and its congener the Hawaiian happy-face spider Theridion grallator, numerous rare patterned morphs. We compare population differentiation estimated from colour phenotypic data to differentiation at neutral amplified fragment length polymorphisms (AFLP) loci and demonstrate that the colour polymorphism appears to be maintained by balancing selection. We also examine the patterns of selection in the genome-wide sample of AFLP loci and compare approaches to detecting signatures of selection in this context. Our results have important implications regarding balancing selection, suggesting that selective agents can act in a similar manner across disparate taxa in globally disjunct locales resulting in parallel evolution of exuberant polymorphism.

Molecular Ecology, 2008

The genetic structure of the clonally reproducing Sudden Oak Death (SOD) pathogen in California w... more The genetic structure of the clonally reproducing Sudden Oak Death (SOD) pathogen in California was investigated using seven variable microsatellites. A total of 35 multilocus genotypes were identified among 292 samples representative of populations from 14 forest sites and of the nursery trade. AMOVA indicated significant genetic variability both within (44.34%) and among populations (55.66%). Spatial autocorrelation analyses indicated that Moran's index of similarity reached a minimum of 0.1 at 350 m, increased to 0.4 at 1500 m and then decreased to zero at 10 km. These results suggest a bimodal pattern of spread, with medium range dispersal (1500-10 000 m) putatively attributed to the presence of strong winds. Lack of genetic structure was identified for three groups of populations. One group notably included the nurseries' population and two forest populations, both linked to early reports of the pathogen. A neighbour-joining analysis based on pairwise Φ ST values indicated that the clade inclusive of the nurseries' populations is basal to all California populations. A network analysis identified three common genotypes as the likely founders of the California infestation and proposes a stepwise model for local evolution of novel genotypes. This was supported by the identification in the same locations of novel genotypes and of their 1-or 2-step parents. We hypothesize that the few undifferentiated population groups indicate historical human spread of the pathogen, while the general presence of genetically structured populations indicates that new infestations are currently generated by rare medium or long-range natural movement of the pathogen, followed by local generation of new genotypes.