Showing papers by "Payal Kapur published in 2020"

HIF-2 Complex Dissociation, Target Inhibition, and Acquired Resistance with PT2385, a First-in-Class HIF-2 Inhibitor, in Patients with Clear Cell Renal Cell Carcinoma.

Abstract: Purpose: The heterodimeric transcription factor HIF-2 is arguably the most important driver of clear cell renal cell carcinoma (ccRCC). Although considered undruggable, structural analyses at the University of Texas Southwestern Medical Center (UTSW, Dallas, TX) identified a vulnerability in the α subunit, which heterodimerizes with HIF1β, ultimately leading to the development of PT2385, a first-in-class inhibitor. PT2385 was safe and active in a first-in-human phase I clinical trial of patients with extensively pretreated ccRCC at UTSW and elsewhere. There were no dose-limiting toxicities, and disease control ≥4 months was achieved in 42% of patients. Patients and Methods: We conducted a prospective companion substudy involving a subset of patients enrolled in the phase I clinical trial at UTSW (n = 10), who were treated at the phase II dose or above, involving multiparametric MRI, blood draws, and serial biopsies for biochemical, whole exome, and RNA-sequencing studies. Results: PT2385 inhibited HIF-2 in nontumor tissues, as determined by a reduction in erythropoietin levels (a pharmacodynamic marker), in all but one patient, who had the lowest drug concentrations. PT2385 dissociated HIF-2 complexes in ccRCC metastases, and inhibited HIF-2 target gene expression. In contrast, HIF-1 complexes were unaffected. Prolonged PT2385 treatment resulted in the acquisition of resistance, and we identified a gatekeeper mutation (G323E) in HIF2α, which interferes with drug binding and precluded HIF-2 complex dissociation. In addition, we identified an acquired TP53 mutation elsewhere, suggesting a possible alternate mechanism of resistance. Conclusions: These findings demonstrate a core dependency on HIF-2 in metastatic ccRCC and establish PT2385 as a highly specific HIF-2 inhibitor in humans. New approaches will be required to target mutant HIF-2 beyond PT2385 or the closely related PT2977 (MK-6482).

Pancreatic tropism of metastatic renal cell carcinoma

Abstract: Renal cell carcinoma (RCC) is characterized by a particularly broad metastatic swath, and, enigmatically, when the pancreas is a destination, the disease is associated with improved survival. Intrigued by this observation, we sought to characterize the clinical behavior, therapeutic implications, and underlying biology. While pancreatic metastases (PM) are infrequent, we identified 31 patients across 2 institutional cohorts and show that improved survival is independent of established prognostic variables, that these tumors are exquisitely sensitive to antiangiogenic agents and resistant to immune checkpoint inhibitors (ICIs), and that they are characterized by a distinctive biology. Primary tumors of patients with PM exhibited frequent PBRM1 mutations, 3p loss, and 5q amplification, along with a lower frequency of aggressive features such as BAP1 mutations and loss of 9p, 14q, and 4q. Gene expression analyses revealed constrained evolution with remarkable uniformity, reduced effector T cell gene signatures, and increased angiogenesis. Similar findings were observed histopathologically. Thus, RCC metastatic to the pancreas is characterized by indolent biology, heightened angiogenesis, and an uninflamed stroma, likely underlying its good prognosis, sensitivity to antiangiogenic therapies, and refractoriness to ICI. These data suggest that metastatic organotropism may be an indicator of a particular biology with prognostic and treatment implications for patients.

Epigenetic silencing of the ubiquitin ligase subunit FBXL7 impairs c-SRC degradation and promotes epithelial-to-mesenchymal transition and metastasis.

Abstract: Epigenetic plasticity is a pivotal factor that drives metastasis. Here, we show that the promoter of the gene that encodes the ubiquitin ligase subunit FBXL7 is hypermethylated in advanced prostate and pancreatic cancers, correlating with decreased FBXL7 mRNA and protein levels. Low FBXL7 mRNA levels are predictive of poor survival in patients with pancreatic and prostatic cancers. FBXL7 mediates the ubiquitylation and proteasomal degradation of active c-SRC after its phosphorylation at Ser 104. The DNA-demethylating agent decitabine recovers FBXL7 expression and limits epithelial-to-mesenchymal transition and cell invasion in a c-SRC-dependent manner. In vivo, FBXL7-depleted cancer cells form tumours with a high metastatic burden. Silencing of c-SRC or treatment with the c-SRC inhibitor dasatinib together with FBXL7 depletion prevents metastases. Furthermore, decitabine reduces metastases derived from prostate and pancreatic cancer cells in a FBXL7-dependent manner. Collectively, this research implicates FBXL7 as a metastasis-suppressor gene and suggests therapeutic strategies to counteract metastatic dissemination of pancreatic and prostatic cancer cells. Moro et al. show that hypermethylation-induced silencing of the ubiquitin ligase FBXL7 rescues c-SRC from ubiquitin-mediated degradation and enhances epithelial-to-mesenchymal transition and metastasis.

Acute interstitial nephritis, a potential predictor of response to immune checkpoint inhibitors in renal cell carcinoma.

Abstract: Immune checkpoint inhibitors (ICIs) such as nivolumab and ipilimumab have improved outcomes in metastatic renal cell carcinoma (mRCC) patients, but they are also associated with immune-related adverse events (irAEs). As observed in melanoma, we hypothesized that patients experiencing an autoimmune reaction directed against the tissue of origin may be more likely to benefit from ICI. Specifically, we asked whether patients with immune-related acute interstitial nephritis (irAIN) exhibited improved outcomes. Using Kidney Cancer Explorer (KCE), a data portal and i2b2-based central database for clinical, pathological and experimental genetic data, we systematically identified all patients with mRCC at UT Southwestern Medical Center (UTSW) from 2014-2018 who received at least one dose of ICI. More recent cases were identified through a provider query. We extracted creatinine (Cr) values at baseline and over the entirety of each patient ICI treatment course using KCE. Patients with ≥ 1.5-fold Cr increase over baseline were investigated. The likelihood of irAIN was determined based on the work-up (biopsy, if available), or by clinical criteria (timing of kidney injury, exclusion of other etiologies, treatment with immunosuppressants and response). We identified 177 mRCC patients who received at least one dose of ICI, 36 of whom had ≥ 1.5-fold increase in Cr over baseline while on treatment. Of those, two had biopsy-proven irAIN and one was clinically diagnosed, resulting in an incidence of 1.7%. One additional biopsy-proven case past 2018 was identified through a provider query, for a total of four patients. Two received combination nivolumab and ipilimumab in the first line, whereas the remaining received nivolumab after first line therapy. irAIN onset ranged from 1.5 to 12 months. All four patients stopped ICI with recovery of renal function, at least partially, three after receiving systemic steroids. Notably, all four patients had a deep response. In conclusion, irAIN is a rare event, but it may portend a higher likelihood of response. One possible explanation is antigenic overlap between normal renal tubular cells and tumor cells.

What morphology can teach us about renal cell carcinoma clonal evolution

Abstract: While cancer is a clonal process, cumulative evidence suggest that tumors are rather heterogenous and are composed of multiple genetically-distinct subclones that arise at different times and either persist and co-exist, expand and evolve, or are eliminated. A paradigm of tumor heterogeneity is renal cell carcinoma (RCC). By exploiting morphological traits and building upon a framework around three axes (architecture, cytology and the microenvironment), we review recent advances in our understanding of RCC evolution leading to an integrated molecular genetic and morphologic evolutionary model with both prognostic and therapeutic implications. The ability to predict cancer evolution may have profound implications for clinical care and is central to oncology.

Predictive capacity of miRNA-375 in identifying teratoma in post-chemotherapy retroperitoneal lymph node dissection (PC-RPLND).

Abstract: 416Background: Traditional tumor markers for testicular germ cell tumor (TGCT), lactate dehydrogenase (LDH), beta-human chorionic gonadotropin (hCG), and alpha-fetoprotein (AFP), have limited sensi...

Anticancer Efficacy of Oral Docetaxel Nanoformulation for Metronomic Chemotherapy in Metastatic Lung Cancer.

Abstract: Metronomic chemotherapy, giving low doses of chemotherapeutics (e.g., docetaxel) on a frequent schedule over a long time, may improve outcomes and reduce side effects for cancer patients. Oral medications are vital for applying metronomic chemotherapy. However, low solubility, low absorption, low drug availability in the targeted tissue, and side effects limit the development of oral chemotherapeutics. Many chemotherapeutics are intravenously delivered. In this work, we developed a new docetaxel granule that produces docetaxel-loaded in situ self-assembled nanoparticle (180 nm) upon contact with water. The process of manufacturing docetaxel granules is scalable in industrial settings. The lung selectivity of docetaxel granule was observed in animals. The mechanistic studies demonstrated the nanoparticle bound with red blood cells, which selectively delivers docetaxel to the lungs. Finally, docetaxel granule (5 mg/kg twice per week) can profoundly inhibit the tumor growth of lung-metastatic cancer xenograft model over 24 days. The material-based lungselective oral nanoformulation provides an opportunity for conventionally intravenous chemotherapy drugs to be easily applied in oral administration for metronomic chemotherapy for cancer patients with lung cancers.

PTRF independently predicts progression and survival in multiracial upper tract urothelial carcinoma following radical nephroureterectomy

Abstract: Objectives Polymerase I and transcript release factor (PTRF) has been implicated in cancer biology but its role in upper tract urothelial carcinoma (UTUC) is unknown. From a pilot transcriptome, we identified PTRF was significantly upregulated in high stage UTUC. Bladder cancer transcriptome from The Cancer Genome Atlas (TCGA) supported our finding and high PTRF level also predicted poor survival. We, therefore, investigated the correlation of PTRF with patients’ clinicopathologic characteristics and outcomes in a multiracial UTUC cohort. Materials and methods By immunohistochemical staining, PTRF expression was determined using H-score. PTRF expression of 575 UTUCs from 8 institutions, including 118 Asians and 457 Caucasians, was compared with various clinicopathologic parameters. Human urothelial cancer cell lines were used to evaluate the level of PTRF protein and mRNA expression, and PTRF transcript level was assessed in fresh samples from 12 cases of the cohort. The impact of PTRF expression on disease progression, cancer-specific death and overall mortality was also examined. Results High PTRF expression was significantly associated with multifocality (P = 0.023), high pathologic tumor stage (P Conclusions Results indicate that PTRF is a predictive biomarker for progression and survival and an independent prognosticator of UTUC. Elevated PTRF could probably propel clinically aggressive disease and serve as a potential therapeutic target for UTUC.

First Do No Harm: A Cautious, Risk-adapted Approach to Testicular Cancer Patients.

Abstract: Current guidelines regarding treatment for germ-cell tumors (GCTs) emphasizes cautious progression focusing on stage-specific treatments. Presented herein is the case of a 30-year-old man who, through monitoring of serum alpha-fetoprotein (AFP) levels and surveillance imaging, avoided excessive treatment. This case demonstrates how an experienced clinician, familiar with natural history of GCTs, can appropriately classify level of risk and allow a patient to preserve natural fertility. Furthermore, we highlight the potential for miRNA analysis in staging and management of GCTs. This case serves to underscore the importance of acting with caution in the pursuit of the best outcome for our patients.