Patrick Pilie

University of Texas MD Anderson Cancer Center | MD Anderson · Division of Cancer Medicine

Purpose: To determine the efficacy and safety of risk-adapted combinations of androgen signaling inhibitors and inform disease classifiers for metastatic castration-resistant prostate cancers (mCRPC). Experimental design: In a modular, randomized phase II trial, 192 men were treated with 8 weeks of abiraterone acetate, prednisone and apalutamide...

Purpose Mutations in the ATM gene are common in multiple cancers, but clinical studies of therapies targeting ATM-aberrant cancers have yielded mixed results. Refinement of ATM loss of function (LOF) as a predictive biomarker of response is urgently needed. Experimental Design We present the first disclosure and preclinical development of a novel,...

Pharmacological inhibition of the ataxia telangiectasia and Rad3-related protein serine/threonine kinase (ATR; also known as FRAP-related protein (FRP1)) has emerged as a promising strategy for cancer treatment that exploits synthetic lethal interactions with proteins involved in DNA damage repair, overcomes resistance to other therapies and enhanc...

Purpose: Speckle-type POZ protein (SPOP) is important in DNA damage response (DDR) and maintenance of genomic stability. Somatic heterozygous missense mutations in the SPOP1 substrate-binding cleft are found in up to 15% of prostate cancers. While mutations in SPOP predict for benefit from androgen receptor signaling inhibition (ARSi) therapy, out...

Purpose: Immune checkpoint blockade (ICB) demonstrates durable clinical benefits in a minority of patients with renal cell carcinoma (RCC). We aimed to identify the molecular features that determine the response and develop approaches to enhance the response. Experimental design: We investigated the effects of SET domain-containing protein 2 (SE...

Introduction: ATM loss of function (LOF) in cancer may serve as a predictive biomarker of response for antitumor therapies. However, clinical studies of targeted treatments in ATM-aberrant patients have yielded mixed results; thus, identifying the optimal strategy for selecting patients with ATM LOF tumors remains a critical area of unmet need. Met...

Introduction: Clear cell renal cell carcinoma (ccRCC) displays genomic instability, but lacks mutations in canonical DNA damage response (DDR) genes. Bi-allelic loss of VHL is a near ubiquitous, truncal event in ccRCC development. Herein, we performed preclinical and clinical analysis to understand how VHL loss impacts DDR pathway activity and how...

Cancer cells depend on multiple driver alterations whose oncogenic effects can be suppressed by drug combinations. Discovering effective combination therapies and selecting patients to maximize therapeutic benefit are challenging due to the complexity of the molecular landscape of drug responses. Here, we provide a comprehensive resource of precisi...

Cancer cells depend on multiple driver alterations whose oncogenic effects can be suppressed by drug combinations. Here, we provide a comprehensive resource of precision combination therapies tailored to oncogenic coalterations that are recurrent across patient cohorts. To generate the resource, we developed Recurrent Features Leveraged for Combina...

Purpose: DNA polymerase epsilon is critical to DNA proofreading and replication. Mutations in POLE have been associated with hypermutated tumors and antitumor response to immune checkpoint inhibitor (ICI) therapy. We present a clinicopathologic analysis of patients with advanced cancers harboring POLE mutations, the pattern of co-occurring mutatio...

Treatment with immune checkpoint blockade (ICB) has resulted in durable responses for a subset of patients with cancer, with predictive biomarkers for ICB response originally identified largely in the context of hypermutated cancers. Although recent clinical data have demonstrated clinical responses to ICB in certain patients with nonhypermutated c...

Purpose: Despite significant benefit for other cancer subtypes, immune checkpoint blockade (ICB) therapy has not yet been shown to significantly improve outcomes for men with castration-resistant prostate cancer (CRPC). Prior data have shown that DNA damage response (DDR) deficiency, via genetic alteration and/or pharmacologic induction using DDR...

A non-immunogenic tumor microenvironment (TME) is a significant barrier to immune checkpoint blockade (ICB) response. The impact of Polybromo-1 (PBRM1) on TME and response to ICB in renal cell carcinoma (RCC) remains to be resolved. Here we show that PBRM1/Pbrm1 deficiency reduces the binding of brahma-related gene 1 (BRG1) to the IFNγ receptor 2 (...

Renal medullary carcinoma (RMC) is a highly lethal malignancy that mainly afflicts young individuals of African descent and is resistant to all targeted agents used to treat other renal cell carcinomas. Comprehensive genomic and transcriptomic profiling of untreated primary RMC tissues was performed to elucidate the molecular landscape of these tum...

PBRM1 is a subunit of a SWI/SNF chromatin remodeling complex, and more than 30% of clear cell RCCs show PBRM1 mutations. The function of PBRM1 in tumor immune microenvironment, tumor prognosis and response to immune checkpoint therapies still remain unclear. Here we found that Pbrm1 knockout in mouse Renca RCC cells decreased the activity of IFNγ-S...

Genomic instability is a hallmark of cancer, allowing for cancer initiation, proliferation, and progression through the accumulation of driver mutations. This instability seen in cancer arises due to a variety of factors in the cancer cell itself as well as in the cell’s environment, including endogenous and exogenous stressors leading to DNA damag...

is a subunit of SWI/SNF complex that regulates chromatin accessibility for transcription factors, and more than 30% of clear cell renal cell carcinoma (RCC) contain mutations. Nivolumab (anti-PD-1) showed profound and prolonged response only in a subset of patients with advanced RCC. The impact of loss on response to immunotherapy in RCC patients s...

is a subunit of SWI/SNF complex that regulates chromatin accessibility for transcription factors, and more than 30% of clear cell renal cell carcinoma (RCC) contain mutations. Nivolumab (anti-PD-1) showed profound and prolonged response only in a subset of patients with advanced RCC. The impact of loss on response to immunotherapy in RCC patients s...

668 Background: Several known hereditary cancer syndromes confer an increased risk for genitourinary (GU)-related malignancies. Various guidelines indicate when to refer patients to genetic counseling for GU cancers, but there are limited data on the performance of these guidelines in clinical practice, and the association between testing outcome a...

A mounting body of evidence now indicates that PARP inhibitors have the potential to be used as a foundation for both monotherapy and combination strategies across a wide spectrum of molecular backgrounds and tumor types. While PARP inhibitors as a class display many similarities, critical differences in structure can translate into differences in...

Cancer initiation and progression is the result of an accumulation of mutations. Mutations occurring in cancer tissue are termed somatic, whereas mutations in germline DNA may be passed onto subsequent generations and are often termed hereditary. Deleterious germline mutations in key tumor suppressor genes can lead to hereditary cancer syndromes wh...

PARP inhibitors drive increased DNA damage, particularly in tumors with existing defects in DNA repair. This damage not only promotes immune priming through a range of molecular mechanisms, but also leads to adaptive upregulation of programmed death ligand 1 (PD-L1) expression. In this context, PARP inhibition and programmed cell death 1(PD-1)/PD-L...

Genomic instability is a key hallmark of cancer that arises owing to defects in the DNA damage response (DDR) and/or increased replication stress. These alterations promote the clonal evolution of cancer cells via the accumulation of driver aberrations, including gene copy-number changes, rearrangements and mutations; however, these same defects al...

Background: No approved systemic therapy exists for von Hippel-Lindau disease, an autosomal dominant disorder with pleiotropic organ manifestations that include clear cell renal cell carcinomas; retinal, cerebellar, and spinal haemangioblastomas; pheochromocytomas; pancreatic serous cystadenomas; and pancreatic neuroendocrine tumours. We aimed to...

Next-generation sequencing has revolutionized precision oncology, with paired somatic and germline DNA variant analysis becoming more powerful and more widely accessible for clinical applications. The field of clinical cancer genetics previously relied primarily on a patient’s personal and family medical history to delineate specific hereditary can...

Introduction: Clear cell renal cell carcinoma (ccRCC) displays genomic instability across all tumor stages, indicative of increased replicative stress and defects in DNA damage response (DDR) pathways including homologous repair (HR); however ccRCC does not display mutations in canonical DDR genes. We hypothesized that biallelic loss is sufficient...

Von Hippel-Lindau (VHL) disease is an autosomal dominant disease occurring in 1 in 35,000 births and leads to an increased risk of a phenotypically diverse array of tumor types including, but not limited to, clear cell renal cell carcinoma (ccRCC) and hemangioblastomas (HBs). Previous studies of patients with VHL disease treated with the tyrosine k...

585 Background: Clear cell renal cell carcinoma (ccRCC) displays genomic instability across all tumor stages, indicative of increased replicative stress and defects in DNA damage response (DDR) pathways including homologous repair (HR); however ccRCC does not display mutations in canonical DDR genes and advanced ccRCC is not traditionally sensitive...

Background: Approximately 16% of patients with renal cell carcinomas (RCC) present with stage IV disease at time of diagnosis. Treatment options for metastatic clear cell RCC, the most common histologic subtype, have proliferated over the past decade and include a combination of surgery and systemic therapy. The selection of systemic agent and best...

Background: Prostate cancer has a significant heritable component, and rare deleterious germline variants in certain genes can increase the risk of the disease. The aim of the current study was to describe the prevalence of pathogenic germline variants in cancer-predisposing genes in men with prostate cancer and at least 1 additional primary cance...

4581 Background: Kidney cancer accounts for 2-3% of all new cancers with clear cell renal cell carcinoma (ccRCC) the most common subtype. ccRCC is characterized by a high level of genomic instability, suggesting defective DNA damage repair (DDR). The most frequent genomic alteration in ccRCC involves loss of the 3p chromosomal arm which harbors the...

Cancer initiation and progression is the result of an accumulation of mutations in key tumor suppressor genes, mismatch repair genes, or oncogenes, which impact cancer cell growth, death, and differentiation. Mutations occurring in cancer tissue are termed somatic; whereas, heritable mutations that may be passed onto subsequent generations occur in...

587 Background: Von Hippel-Lindau (VHL) is an autosomal dominant inherited disease occurring in 1 in 35,000 births. Individuals with germline mutations in the VHL gene may phenotypically express a variety of lesions including hemangioblastomas (HBs), pancreatic cysts, renal cysts, and renal cell carcinomas (RCC). Previous studies have shown differe...

Respiratory syncytial virus (RSV) is a common community-acquired pathogen responsible for a substantial disease burden in adults. We investigated outcomes after RSV infection in hospitalized adults over a 3-year period. This single-center, retrospective study identified 174 patients hospitalized with RSV upper or lower respiratory tract infection (...

Ductal carcinoma in situ (DCIS) is a noninvasive, transformed, neoplastic lesion with a significant likelihood, but without certainty, of progressing to invasive breast cancer, although there are molecular and cellular features that have some predictive power for the development of invasive disease. In women who carry deleterious mutations in the B...

http://deepblue.lib.umich.edu/bitstream/2027.42/110634/1/jhm2272.pdf

Normal mammary gland homeostasis requires the coordinated regulation of protein signaling networks. However, we have little prospective information on whether activation of protein signaling occurs in premalignant mammary epithelial cells, as represented by cells with cytological atypia from women who are at high risk for breast cancer. This inform...

Obesity is a well-established risk factor for cancer, accounting for up to 20% of cancer deaths in women. Studies of women with breast cancer have shown obesity to be associated with an increased risk of dying from breast cancer and increased risk of developing distant metastasis. While previous studies have focused on differences in circulating ho...

s: AACR International Conference on Frontiers in Cancer Prevention Research‐‐ Nov 7-10, 2010; Philadelphia, PA Background: Currently we lack the ability to rapidly test new agents to prevent breast cancer. Targeted agents are in clinical testing for treatment of breast cancer but are not being adequately explored for prevention. This is because, w...

Over the last 50 years, the number of cancer related deaths has decreased by only 2%. One of the most promising approaches to reduce breast cancer mortality is to develop tools for early detection and early intervention of breast cancers. Normal mammary gland homeostasis requires the coordinated regulation of signaling networks; whereas, dysregulat...

Only 5% of all breast cancers are the result of BRCA1/2 mutations. Methylation silencing of tumor suppressor genes is well described in sporadic breast cancer; however, its role in familial breast cancer is not known. CpG island promoter methylation was tested in the initial random periareolar fine-needle aspiration sample from 109 asymptomatic wom...

Currently, we lack biomarkers to predict whether high-risk women with mammary atypia will respond to tamoxifen chemoprevention. Thirty-four women with cytologic mammary atypia from the Duke University High-Risk clinic were offered tamoxifen chemoprevention. We tested whether ESR1 promoter hypermethylation and/or estrogen receptor (ER) protein expre...

p16(INK4a) has been appreciated as a key regulator of cell cycle progression and senescence. Cultured human mammary epithelial cells that lack p16(INK4a) activity have been shown to exhibit premalignant phenotypes, such as telomeric dysfunction, centrosomal dysfunction, a sustained stress response, and, most recently, a dysregulation of chromatin r...