Publications by authors named "Alice C Fan"

36 Publications

In Search of Clinical Biomarkers of Response to Checkpoint Inhibitor Therapy in Renal Cell Carcinoma.

JAMA Netw Open 2021 01 4;4(1):e2035120. Epub 2021 Jan 4.

Division of Oncology, Department of Medicine, Stanford University School of Medicine, Stanford, California.

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http://dx.doi.org/10.1001/jamanetworkopen.2020.35120DOI Listing
January 2021

Giant Magnetoresistive Nanosensor Analysis of Circulating Tumor DNA Epidermal Growth Factor Receptor Mutations for Diagnosis and Therapy Response Monitoring.

Clin Chem 2021 Mar;67(3):534-542

Department of Materials Science and Engineering, Stanford University, Stanford, CA, USA.

Background: Liquid biopsy circulating tumor DNA (ctDNA) mutational analysis holds great promises for precision medicine targeted therapy and more effective cancer management. However, its wide adoption is hampered by high cost and long turnaround time of sequencing assays, or by inadequate analytical sensitivity of existing portable nucleic acid tests to mutant allelic fraction in ctDNA.

Methods: We developed a ctDNA Epidermal Growth Factor Receptor (EGFR) mutational assay using giant magnetoresistive (GMR) nanosensors. This assay was validated in 36 plasma samples of non-small cell lung cancer patients with known EGFR mutations. We assessed therapy response through follow-up blood draws, determined concordance between the GMR assay and radiographic response, and ascertained progression-free survival of patients.

Results: The GMR assay achieved analytical sensitivities of 0.01% mutant allelic fraction. In clinical samples, the assay had 87.5% sensitivity (95% CI = 64.0-97.8%) for Exon19 deletion and 90% sensitivity (95% CI = 69.9-98.2%) for L858R mutation with 100% specificity; our assay detected T790M resistance with 96.3% specificity (95% CI = 81.7-99.8%) with 100% sensitivity. After 2 weeks of therapy, 10 patients showed disappearance of ctDNA by GMR (predicted responders), whereas 3 patients did not (predicted nonresponders). These predictions were 100% concordant with radiographic response. Kaplan-Meier analysis showed responders had significantly (P < 0.0001) longer PFS compared to nonresponders (N/A vs. 12 weeks, respectively).

Conclusions: The GMR assay has high diagnostic sensitivity and specificity and is well suited for detecting EGFR mutations at diagnosis and noninvasively monitoring treatment response at the point-of-care.
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http://dx.doi.org/10.1093/clinchem/hvaa307DOI Listing
March 2021

Targeting Metabolic Pathways in Kidney Cancer: Rationale and Therapeutic Opportunities.

Cancer J 2020 Sep/Oct;26(5):407-418

Division of Oncology, Washington University in St. Louis, St. Louis, MO.

Alterations in cellular sugar, amino acid and nucleic acid, and lipid metabolism, as well as in mitochondrial function, are a hallmark of renal cell carcinoma (RCC). The activation of oncogenes such as hypoxia-inducible factor and loss of the von Hippel-Lindau function and other tumor suppressors frequently occur early on during tumorigenesis and are the drivers for these changes, collectively known as "metabolic reprogramming," which promotes cellular growth, proliferation, and stress resilience. However, tumor cells can become addicted to reprogrammed metabolism. Here, we review the current knowledge of metabolic addictions in clear cell RCC, the most common form of RCC, and to what extent this has created therapeutic opportunities to interfere with such altered metabolic pathways to selectively target tumor cells. We highlight preclinical and emerging clinical data on novel therapeutics targeting metabolic traits in clear cell RCC to provide a comprehensive overview on current strategies to exploit metabolic reprogramming clinically.
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http://dx.doi.org/10.1097/PPO.0000000000000472DOI Listing
September 2020

Routine Plasma-Based Genotyping to Comprehensively Detect Germline, Somatic, and Reversion Mutations among Patients with Advanced Solid Tumors.

Clin Cancer Res 2020 06 7;26(11):2546-2555. Epub 2020 Feb 7.

Northwestern University Feinberg School of Medicine, Chicago, Illinois.

Purpose: PARP inhibitors (PARPi) are efficacious in multiple cancers harboring germline (and possibly somatic) mutations. Acquired reversions can restore function, causing resistance to PARPi and/or platinum-based chemotherapy. The optimal method of identifying patients with germline, somatic, and/or reversion mutations in has not been established. Next-generation sequencing (NGS) of cell-free DNA (cfDNA) provides a platform to identify these three types of mutations.

Experimental Design: Patients with advanced breast, ovarian, prostate, or pancreatic cancer were tested using a clinically validated 73-gene cfDNA assay that evaluates single-nucleotide variants and insertion-deletion mutations (indels) in , and distinguishes somatic/reversion from germline mutations with high accuracy.

Results: Among 828 patients, one or more deleterious mutations were detected in 60 (7.2%) patients, including germline ( = 42) and somatic ( = 18) mutations. Common coexisting mutations included (61.6%), (30%), (26.6%), (15%), and (11.5%). Polyclonal reversion mutations (median, 5) were detected in 9 of 42 (21.4%) germline mutant patients, the majority (77.7%) of whom had prior PARPi exposure (median duration, 10 months). Serial cfDNA demonstrated emergence of reversion mutations under therapeutic pressure from initial PARPi exposure, which contributed to subsequent resistance to PARPi and platinum therapy.

Conclusions: cfDNA NGS identified high rates of therapeutically relevant mutations without foreknowledge of germline or tissue-based testing results, including deleterious somatic mutations missed by germline testing and reversion mutations that can have important treatment implications. Further research is needed to confirm clinical utility of these findings to guide precision medicine approaches for patients with advanced malignancies.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-2933DOI Listing
June 2020

A Clinicopathologic and Molecular Analysis of Fumarate Hydratase-deficient Renal Cell Carcinoma in 32 Patients.

Am J Surg Pathol 2020 01;44(1):98-110

Department of Pathology, Stanford Medical Center, Stanford, CA.

Fumarate hydratase-deficient renal cell carcinoma (FH-deficient RCC) is a rare and recently described entity associated with hereditary leiomyomatosis and RCC syndrome. FH-deficient RCC may show variable clinical and pathologic findings, but commonly presents with locally advanced and metastatic disease and carries a poor prognosis. We identified 32 patients with FH-deficient RCC, confirmed by FH immunohistochemistry (IHC) and/or FH mutation analysis, and performed a retrospective review of the clinical and pathologic features. Median age at presentation was 43 years (range, 18 to 69 y), and the M:F ratio was 2.2:1. Median tumor size was 6.5 cm (range, 2.5 to 28 cm), and 71% presented at stage ≥pT3a. After a median follow-up of 16 months (range, 1 to 118 mo) in 26 patients, 19% showed no evidence of disease, 31% were alive with disease, and 50% were dead of disease. The vast majority of cases showed multiple histologic growth patterns, with papillary (52%) being the most common predominant pattern, followed by solid (21%), cribriform/sieve-like (14%), sarcomatoid (3%), tubular (3%), cystic (3%), and low-grade oncocytic (3%). Viral inclusion-like macronucleoli with perinucleolar clearing were present in almost all cases (96%). All cases were evaluated using FH IHC, and 3 cases (9%) showed retained FH expression. Nineteen cases had germline or tumor mutation analysis confirming a FH mutation, with 79% (11/14) of cases showing mutations within coding regions and 21% (3/14) showing mutations within intronic splice-sites. By IHC, 97% (32/33) of cases were negative for CK7, 93% (27/29) were negative for p63, and 52% (15/29) were negative for GATA3. All cases stained were positive for PAX8 and showed retained succinate dehydrogenase B expression. Our overall findings show that FH-deficient RCC is considerably heterogenous in morphology and frequently behaves aggressively. Suspicion for this entity should be raised even in the absence of predominantly papillary architecture and characteristic nucleolar features. We have included cases with uncommonly seen features, including 4 cases with predominantly cribriform/sieve-like architecture as well as one case with pure low-grade oncocytic morphology (9 y of clinical follow-up without evidence of disease). Although FH IHC is a useful tool for identifying cases of FH-deficient RCC, not all cases of FH-deficient RCC show loss of FH staining, and FH mutation analysis should be considered for patients with suspicious clinical or pathologic features, even in cases with retained FH IHC expression.
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http://dx.doi.org/10.1097/PAS.0000000000001372DOI Listing
January 2020

Multiregion Quantification of Extracellular Signal-regulated Kinase Activity in Renal Cell Carcinoma.

Eur Urol Oncol 2020 06 20;3(3):360-364. Epub 2018 Nov 20.

Division of Oncology, Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA; The Kidney Cancer Research Program, Stanford University School of Medicine, Stanford, CA, USA; Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA; Bio-X, Stanford University, Stanford, CA, USA. Electronic address:

To personalize treatment for renal cell carcinoma (RCC), it would be ideal to confirm the activity of druggable protein pathways within individual tumors. We have developed a high-resolution nanoimmunoassay (NIA) to measure protein activity with high precision in scant specimens (eg, fine needle aspirates [FNAs]). Here, we used NIA to determine whether protein activation varied in different regions of RCC tumors. Since most RCC therapies target angiogenesis by inhibiting the vascular endothelial growth factor (VEGF) receptor, we quantified phosphorylation of extracellular signal-regulated kinase (ERK), a downstream effector of the VEGF signaling pathway. In 90 ex vivo FNA biopsies sampled from multiple regions of 38 primary clear cell RCC tumors, ERK phosphorylation differed among patients. In contrast, within individual patients, we found limited intratumoral heterogeneity of ERK phosphorylation. Our results suggest that measuring ERK in a single FNA may be representative of ERK activity in different regions of the same tumor. As diagnostic and therapeutic protein biomarkers are being sought, NIA measurements of protein signaling may increase the clinical utility of renal mass biopsy and allow for the application of precision oncology for patients with localized and advanced RCC. PATIENT SUMMARY: In this report, we applied a new approach to measure the activity of extracellular signal-regulated kinase (ERK), a key cancer signaling protein, in different areas within kidney cancers. We found that ERK activity varied between patients, but that different regions within individual kidney tumors showed similar ERK activity. This suggests that a single biopsy of renal cell carcinoma may be sufficient to measure protein signaling activity to aid in precision oncology approaches.
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http://dx.doi.org/10.1016/j.euo.2018.09.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6697234PMC
June 2020

Postmarketing Analysis of Sipuleucel-T-The Importance of Real-World Data.

JAMA Netw Open 2019 08 2;2(8):e199233. Epub 2019 Aug 2.

Department of Urology, Stanford University School of Medicine, Stanford, California.

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http://dx.doi.org/10.1001/jamanetworkopen.2019.9233DOI Listing
August 2019

Time on Therapy for at Least Three Months Correlates with Overall Survival in Metastatic Renal Cell Carcinoma.

Cancers (Basel) 2019 Jul 17;11(7). Epub 2019 Jul 17.

Division of Oncology, Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.

With 15 drugs currently approved for the treatment of metastatic renal cell carcinoma (mRCC) and even more combination regimens with immunotherapy on the horizon, there remains a distinct lack of molecular biomarkers for therapeutic efficacy. Our study reports on real-world clinical outcomes of mRCC patients from a tertiary academic medical center treated with empirically selected standard-of-care therapy. We utilized the Stanford Renal Cell Carcinoma Database (RCCD) to report on various outcome measures, including overall survival (OS) and the median number of lines of targeted therapies received from the time of metastatic diagnosis. We found that most metastatic patients did not survive long enough to attempt even half of the available targeted therapies. We also noted that patients who failed to receive a clinical benefit within the first two lines of therapy could still go on to experience clinical benefit in later lines of therapy. The term, "clinical benefit" was assigned to a line of therapy if a patient remained on drug treatment for three months or longer. Moreover, patients with clinical benefit in at least one line of therapy experienced significantly longer OS compared to those who did not have clinical benefit in at least one line of therapy. Developing biomarkers that identify patients who will receive clinical benefit in individual lines of therapy is one potential strategy for achieving rational drug sequencing in mRCC.
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http://dx.doi.org/10.3390/cancers11071000DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6678132PMC
July 2019

Early Changes in CT Perfusion Parameters: Primary Renal Carcinoma Versus Metastases After Treatment with Targeted Therapy.

Cancers (Basel) 2019 04 30;11(5). Epub 2019 Apr 30.

Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA 94305, USA.

Computed tomography (CT) perfusion is a novel imaging method to determine tumor perfusion using a low-dose CT technique to measure iodine concentration at multiple time points. We determined if early changes in perfusion differ between primary renal tumors and metastatic tumor sites in patients with renal cell carcinoma (RCC) receiving targeted anti-angiogenic therapy. A total of 10 patients with advanced RCC underwent a CT perfusion scan at treatment baseline and at one week after initiating treatment. Perfusion measurements included blood volume (BV), blood flow (BF), and flow extraction product (FEP) in a total of 13 lesions (six primary RCC tumors, seven RCC metastases). Changes between baseline and week 1 were compared between tumor locations: primary kidney tumors vs metastases. Metastatic lesions had a greater decrease in BF (average BF difference ± standard deviation (SD): -75.0 mL/100 mL/min ± 81) compared to primary kidney masses (-25.5 mL/100 mL/min ± 35). Metastatic tumors had a wider variation of change in BF, BV and FEP measures compared to primary renal tumors. Tumor diameters showed little change after one week, but early perfusion changes are evident, especially in metastatic lesions compared to primary lesions. Future studies are needed to determine if these changes can predict which patients are benefiting from targeted therapy.
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http://dx.doi.org/10.3390/cancers11050608DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6562747PMC
April 2019

The 'Achilles Heel' of Metabolism in Renal Cell Carcinoma: Glutaminase Inhibition as a Rational Treatment Strategy.

Kidney Cancer 2019 Feb 5;3(1):15-29. Epub 2019 Feb 5.

Division of Oncology, Department of Medicine, Stanford University School of Medicine, CA, USA.

An important hallmark of cancer is 'metabolic reprogramming' or the rewiring of cellular metabolism to support rapid cell proliferation [1-5]. Metabolic reprogramming through oncometabolite-mediated transformation or activation of oncogenes in renal cell carcinoma (RCC) globally impacts energy production as well as glucose and glutamine utilization in RCC cells, which can promote dependence on glutamine supply to support cell growth and proliferation [6, 7]. Novel inhibitors of glutaminase, a key enzyme in glutamine metabolism, target glutamine addiction as a viable treatment strategy in metastatic RCC (mRCC). Here, we review glutamine metabolic pathways and how changes in cellular glutamine utilization enable the progression of RCC. This overview provides scientific rationale for targeting this pathway in patients with mRCC. We will summarize the current understanding of cellular and molecular mechanisms underlying anti-tumor efficacy of glutaminase inhibitors in RCC, provide an overview of clinical efforts targeting glutaminase in mRCC, and review approaches for identifying biomarkers for patient stratification and detecting therapeutic response early on in patients treated with this novel class of anti-cancer drug. Ultimately, results of ongoing clinical trials will demonstrate whether glutaminase inhibition can be a worthy addition to the current armamentarium of drugs used for patients with mRCC.
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http://dx.doi.org/10.3233/KCA-180043DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6400133PMC
February 2019

F-FPPRGD PET/CT in patients with metastatic renal cell cancer.

Eur J Nucl Med Mol Imaging 2019 Jul 8;46(7):1518-1523. Epub 2019 Mar 8.

Division of Nuclear Medicine and Molecular Imaging, Department of Radiology, Stanford University, 300 Pasteur Drive, Stanford, CA, 94305-5281, USA.

Purpose: The usefulness of positron emission tomography/computed tomography (PET/CT) using (F)-2-fluoropropionyl-labeled PEGylated dimeric arginine-glycine-aspartic acid peptide [PEG3-E{c(RGDyk)}2] (F-FPPRGD) in patients with metastatic renal cell cancer (mRCC) has not been evaluated; therefore, we were prompted to conduct this pilot study.

Methods: Seven patients with mRCC were enrolled in this prospective study. F-FPPRGD and 2-deoxy-2-(F)fluoro-D-glucose (F-FDG) PET/CT images were evaluated in a per-lesion analysis. Maximum standardized uptake value (SUV) and tumor-to-background ratio (T/B) were measured for all detected lesions, both before and after starting antiangiogenic therapy.

Results: Sixty lesions in total were detected in this cohort. SUV from F-FPPRGD PET/CT was lower than that from F-FDG PET/CT (4.4 ± 2.9 vs 7.8 ± 5.6, P < 0.001). Both SUV and T/B from F-FPPRGD PET/CT decreased after starting antiangiogenic therapy (SUV, 4.2 ± 3.2 vs 2.6 ± 1.4, P = 0.003; T/B, 3.7 ± 3.2 vs 1.5 ± 0.8, P < 0.001). Average changes in SUV and T/B were - 29.3 ± 23.6% and - 48.1 ± 28.3%, respectively.

Conclusions: F-FPPRGD PET/CT may be an useful tool for monitoring early response to antiangiogenic therapy in patients with mRCC. These preliminary results need to be confirmed in larger cohorts.
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http://dx.doi.org/10.1007/s00259-019-04295-7DOI Listing
July 2019

Monitoring Neutropenia for Cancer Patients at the Point of Care.

Small Methods 2017 Sep 9;1(9). Epub 2017 Aug 9.

Demirci Bio-Acoustic-MEMS in Medicine (BAMM) Laboratory, Stanford University School of Medicine.

Neutrophils have a critical role in regulating the immune system. The immune system is compromised during chemotherapy, increasing infection risks and imposing a need for regular monitoring of neutrophil counts. Although commercial hematology analyzers are currently used in clinical practice for neutrophil counts, they are only available in clinics and hospitals, use large blood volumes, and are not available at the point of care (POC). Additionally, phlebotomy and blood processing require trained personnel, where patients are often admitted to hospitals when the infections are at late stage due to lack of frequent monitoring. Here, a reliable method is presented that selectively captures and quantifies white blood cells (WBCs) and neutrophils from a finger prick volume of whole blood by integrating microfluidics with high-resolution imaging algorithms. The platform is compact, portable, and easy to use. It captures and quantifies WBCs and neutrophils with high efficiency (>95%) and specificity (>95%) with an overall 4.2% bias compared to standard testing. The results from a small cohort of patients ( = 11 healthy, = 5 lung and kidney cancer) present a unique disposable cell counter, demonstrating the ability of this tool to monitor neutrophil and WBC counts within clinical or in resource-constrained environments.
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http://dx.doi.org/10.1002/smtd.201700193DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6364993PMC
September 2017

High-throughput screening of tyrosine kinase inhibitor cardiotoxicity with human induced pluripotent stem cells.

Sci Transl Med 2017 02;9(377)

Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94305, USA.

Tyrosine kinase inhibitors (TKIs), despite their efficacy as anticancer therapeutics, are associated with cardiovascular side effects ranging from induced arrhythmias to heart failure. We used human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), generated from 11 healthy individuals and 2 patients receiving cancer treatment, to screen U.S. Food and Drug Administration-approved TKIs for cardiotoxicities by measuring alterations in cardiomyocyte viability, contractility, electrophysiology, calcium handling, and signaling. With these data, we generated a "cardiac safety index" to reflect the cardiotoxicities of existing TKIs. TKIs with low cardiac safety indices exhibit cardiotoxicity in patients. We also derived endothelial cells (hiPSC-ECs) and cardiac fibroblasts (hiPSC-CFs) to examine cell type-specific cardiotoxicities. Using high-throughput screening, we determined that vascular endothelial growth factor receptor 2 (VEGFR2)/platelet-derived growth factor receptor (PDGFR)-inhibiting TKIs caused cardiotoxicity in hiPSC-CMs, hiPSC-ECs, and hiPSC-CFs. With phosphoprotein analysis, we determined that VEGFR2/PDGFR-inhibiting TKIs led to a compensatory increase in cardioprotective insulin and insulin-like growth factor (IGF) signaling in hiPSC-CMs. Up-regulating cardioprotective signaling with exogenous insulin or IGF1 improved hiPSC-CM viability during cotreatment with cardiotoxic VEGFR2/PDGFR-inhibiting TKIs. Thus, hiPSC-CMs can be used to screen for cardiovascular toxicities associated with anticancer TKIs, and the results correlate with clinical phenotypes. This approach provides unexpected insights, as illustrated by our finding that toxicity can be alleviated via cardioprotective insulin/IGF signaling.
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http://dx.doi.org/10.1126/scitranslmed.aaf2584DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5409837PMC
February 2017

KB004, a first in class monoclonal antibody targeting the receptor tyrosine kinase EphA3, in patients with advanced hematologic malignancies: Results from a phase 1 study.

Leuk Res 2016 11 28;50:123-131. Epub 2016 Sep 28.

H Lee Moffitt Cancer Center & Research Institute, Tampa, FL, United States.

EphA3 is an Ephrin receptor tyrosine kinase that is overexpressed in most hematologic malignancies. We performed a first-in-human multicenter phase I study of the anti-EphA3 monoclonal antibody KB004 in refractory hematologic malignancies in order to determine safety and tolerability, along with the secondary objectives of pharmacokinetics (PK) and pharmacodynamics (PD) assessments, as well as preliminary assessment of efficacy. Patients were enrolled on a dose escalation phase (DEP) initially, followed by a cohort expansion phase (CEP). KB004 was administered by intravenous infusion on days 1, 8, and 15 of each 21-day cycle in escalating doses. A total of 50 patients (AML 39, MDS/MPN 3, MDS 4, DLBCL 1, MF 3) received KB004 in the DEP; an additional 14 patients were treated on the CEP (AML 8, MDS 6). The most common toxicities were transient grade 1 and grade 2 infusion reactions (IRs) in 79% of patients. IRs were dose limiting above 250mg. Sustained exposure exceeding the predicted effective concentration (1ug/mL) and covering the 7-day interval between doses was achieved above 190mg. Responses were observed in patients with AML, MF, MDS/MPN and MDS. In this study, KB004 was well tolerated and clinically active when given as a weekly infusion.
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http://dx.doi.org/10.1016/j.leukres.2016.09.012DOI Listing
November 2016

BIM mediates oncogene inactivation-induced apoptosis in multiple transgenic mouse models of acute lymphoblastic leukemia.

Oncotarget 2016 May;7(19):26926-34

Division of Oncology, Department of Medicine and Pathology, Stanford University, Stanford, CA, United States of America.

Oncogene inactivation in both clinical targeted therapies and conditional transgenic mouse cancer models can induce significant tumor regression associated with the robust induction of apoptosis. Here we report that in MYC-, RAS-, and BCR-ABL-induced acute lymphoblastic leukemia (ALL), apoptosis upon oncogene inactivation is mediated by the same pro-apoptotic protein, BIM. The induction of BIMin the MYC- and RAS-driven leukemia is mediated by the downregulation of miR-17-92. Overexpression of miR-17-92 blocked the induction of apoptosis upon oncogene inactivation in the MYC and RAS-driven but not in the BCR-ABL-driven ALL leukemia. Hence, our results provide novel insight into the mechanism of apoptosis upon oncogene inactivation and suggest that induction of BIM-mediated apoptosis may be an important therapeutic approach for ALL.
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http://dx.doi.org/10.18632/oncotarget.8731DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5053622PMC
May 2016

Oncogene withdrawal engages the immune system to induce sustained cancer regression.

J Immunother Cancer 2014 15;2:24. Epub 2014 Jul 15.

Division of Oncology, Departments of Medicine and Pathology, Stanford University School of Medicine, 269 Campus Drive, CCSR 1105, Stanford 94305-5151, CA, USA.

The targeted inactivation of a single oncogene can induce dramatic tumor regression, suggesting that cancers are "oncogene addicted." Tumor regression following oncogene inactivation has been thought to be a consequence of restoration of normal physiological programs that induce proliferative arrest, apoptosis, differentiation, and cellular senescence. However, recent observations illustrate that oncogene addiction is highly dependent upon the host immune cells. In particular, CD4(+) helper T cells were shown to be essential to the mechanism by which MYC or BCR-ABL inactivation elicits "oncogene withdrawal." Hence, immune mediators contribute in multiple ways to the pathogenesis, prevention, and treatment of cancer, including mechanisms of tumor initiation, progression, and surveillance, but also oncogene inactivation-mediated tumor regression. Data from both the bench and the bedside illustrates that the inactivation of a driver oncogene can induce activation of the immune system that appears to be essential for sustained tumor regression.
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http://dx.doi.org/10.1186/2051-1426-2-24DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4118610PMC
August 2014

Alteration of the lipid profile in lymphomas induced by MYC overexpression.

Proc Natl Acad Sci U S A 2014 Jul 3;111(29):10450-5. Epub 2014 Jul 3.

Department of Chemistry, Stanford University, Stanford, CA 94305-5080;

Overexpression of the v-myc avian myelocytomatosis viral oncogene homolog (MYC) oncogene is one of the most commonly implicated causes of human tumorigenesis. MYC is known to regulate many aspects of cellular biology including glucose and glutamine metabolism. Little is known about the relationship between MYC and the appearance and disappearance of specific lipid species. We use desorption electrospray ionization mass spectrometry imaging (DESI-MSI), statistical analysis, and conditional transgenic animal models and cell samples to investigate changes in lipid profiles in MYC-induced lymphoma. We have detected a lipid signature distinct from that observed in normal tissue and in rat sarcoma-induced lymphoma cells. We found 104 distinct molecular ions that have an altered abundance in MYC lymphoma compared with normal control tissue by statistical analysis with a false discovery rate of less than 5%. Of these, 86 molecular ions were specifically identified as complex phospholipids. To evaluate whether the lipid signature could also be observed in human tissue, we examined 15 human lymphoma samples with varying expression levels of MYC oncoprotein. Distinct lipid profiles in lymphomas with high and low MYC expression were observed, including many of the lipid species identified as significant for MYC-induced animal lymphoma tissue. Our results suggest a relationship between the appearance of specific lipid species and the overexpression of MYC in lymphomas.
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http://dx.doi.org/10.1073/pnas.1409778111DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4115527PMC
July 2014

BCL-2 inhibition with ABT-737 prolongs survival in an NRAS/BCL-2 mouse model of AML by targeting primitive LSK and progenitor cells.

Blood 2013 Oct 13;122(16):2864-76. Epub 2013 Aug 13.

Institut National de la Santé et de la Recherche Médicale U940, Paris, France;

Myelodysplastic syndrome (MDS) transforms into an acute myelogenous leukemia (AML) with associated increased bone marrow (BM) blast infiltration. Using a transgenic mouse model, MRP8[NRASD12/hBCL-2], in which the NRAS:BCL-2 complex at the mitochondria induces MDS progressing to AML with dysplastic features, we studied the therapeutic potential of a BCL-2 homology domain 3 mimetic inhibitor, ABT-737. Treatment significantly extended lifespan, increased survival of lethally irradiated secondary recipients transplanted with cells from treated mice compared with cells from untreated mice, with a reduction of BM blasts, Lin-/Sca-1(+)/c-Kit(+), and progenitor populations by increased apoptosis of infiltrating blasts of diseased mice assessed in vivo by technicium-labeled annexin V single photon emission computed tomography and ex vivo by annexin V/7-amino actinomycin D flow cytometry, terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling, caspase 3 cleavage, and re-localization of the NRAS:BCL-2 complex from mitochondria to plasma membrane. Phosphoprotein analysis showed restoration of wild-type (WT) AKT or protein kinase B, extracellular signal-regulated kinase 1/2 and mitogen-activated protein kinase patterns in spleen cells after treatment, which showed reduced mitochondrial membrane potential. Exon specific gene expression profiling corroborates the reduction of leukemic cells, with an increase in expression of genes coding for stem cell development and maintenance, myeloid differentiation, and apoptosis. Myelodysplastic features persist underscoring targeting of BCL-2-mediated effects on MDS-AML transformation and survival of leukemic cells.
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http://dx.doi.org/10.1182/blood-2012-07-445635DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3799000PMC
October 2013

Real-time nanoscale proteomic analysis of the novel multi-kinase pathway inhibitor rigosertib to measure the response to treatment of cancer.

Expert Opin Investig Drugs 2013 Nov 12;22(11):1495-509. Epub 2013 Aug 12.

Stanford University School of Medicine, Division of Oncology, Departments of Medicine and Pathology , Stanford, CA , USA

Introduction: Rigosertib (ON01910.Na), is a targeted therapeutic that inhibits multiple kinases, including PI3K and PIk-1. Rigosertib has been found to induce the proliferative arrest and apoptosis of myeloblasts but not of other normal hematopoietic cells. Rigosertib has significant clinical activity as a therapy for patients with high-risk myelodysplastic syndrome who are otherwise refractory to DNA methyltransferase inhibitors. Moreover, rigosertib has potential clinical activity in a multitude of solid tumors.

Areas Covered: The objective of this review is to evaluate the mechanism of activity, efficacy and dosing of rigosertib. Furthermore, the challenge in the clinical development of rigosertib, to identify the specific patients that are most likely to benefit from this therapeutic agent, is discussed. A PubMed search was performed using the following key words: rigosertib and ON01910.Na.

Expert Opinion: We describe the application of a novel nanoscale proteomic assay, the nanoimmunoassay, a tractable approach for measuring the activity and predicting the efficacy of rigosertib, in real-time, using limited human clinical specimens. Our strategy suggests a possible paradigm where proteomic analysis during the pre-clinical and clinical development of a therapy can be used to uncover biomarkers for the analysis and prediction of efficacy in human patients.
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http://dx.doi.org/10.1517/13543784.2013.829453DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4111569PMC
November 2013

Cryptococcal osteomyelitis and meningitis in a patient with non-hodgkin's lymphoma treated with PEP-C.

BMJ Case Rep 2012 Sep 7;2012. Epub 2012 Sep 7.

Department of Internal Medicine, Scripps Clinic/Green Hospital, La Jolla, California, USA.

The authors present the first case report of a patient with lymphoma who developed disseminated cryptococcal osteomyelitis and meningitis while being treated with the PEP-C (prednisone, etoposide, procarbazine and cyclophosphamide) chemotherapy regimen. During investigation of fever and new bony lesions, fungal culture from a rib biopsy revealed that the patient had cryptococcal osteomyelitis. Further evaluation demonstrated concurrent cryptococcal meningitis. The patient's disseminated cryptococcal infections completely resolved after a full course of antifungal treatment. Cryptococcal osteomyelitis is itself an extremely rare diagnosis, and the unique presentation with concurrent cryptococcal meningitis in our patient with lymphoma was likely due to his PEP-C treatment. It is well recognised that prolonged intensive chemotherapeutic regimens place patients at risk for atypical infections; yet physicians should recognise that even chronic low-dose therapies can put patients at risk for fungal infections. Physicians should consider fungal infections as part of the infectious investigation of a lymphopaenic patient on PEP-C.
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http://dx.doi.org/10.1136/bcr.08.2011.4578DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3448757PMC
September 2012

"Picolog," a synthetically-available bryostatin analog, inhibits growth of MYC-induced lymphoma in vivo.

Oncotarget 2012 Jan;3(1):58-66

Departments of Chemistry and Chemical and Systems Biology, Stanford University, Stanford, CA 94305-5080.

Bryostatin 1 is a naturally occurring complex macrolide with potent anti-neoplastic activity. However, its extremely low natural occurrence has impeded clinical advancement. We developed a strategy directed at the design of simplified and synthetically more accessible bryostatin analogs. Our lead analog, "picolog", can be step-economically produced. Picolog, compared to bryostatin, exhibited superior growth inhibition of MYC-induced lymphoma in vitro. A key mechanism of picolog's (and bryostatin's) activity is activation of PKC. A novel nano-immunoassay (NIA) revealed that picolog treatment increased phospho-MEK2 in the PKC pathway. Moreover, the inhibition of PKC abrogated picolog's activity. Finally, picolog was highly potent at 100 micrograms/kg and well tolerated at doses ranging from 100 micrograms/kg to 1 milligram/kg in vivo for the treatment of our aggressive model of MYC-induced lymphoma. We provide the first in vivo validation that the bryostatin analog, picolog, is a potential therapeutic agent for the treatment of cancer and other diseases.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3292892PMC
http://dx.doi.org/10.18632/oncotarget.438DOI Listing
January 2012

Treatment of higher risk myelodysplastic syndrome patients unresponsive to hypomethylating agents with ON 01910.Na.

Leuk Res 2012 Jan 14;36(1):98-103. Epub 2011 Sep 14.

Department of Medicine (Hematology), Stanford University Cancer Center, Stanford, CA, USA.

In a Phase I/II clinical trial, 13 higher risk red blood cell-dependent myelodysplastic syndrome (MDS) patients unresponsive to hypomethylating therapy were treated with the multikinase inhibitor ON 01910.Na. Responses occurred in all morphologic, prognostic risk and cytogenetic subgroups, including four patients with marrow complete responses among eight with stable disease, associated with good drug tolerance. In a subset of patients, a novel nanoscale immunoassay showed substantially decreased AKT2 phosphorylation in CD34+ marrow cells from patients responding to therapy but not those who progressed on therapy. These data demonstrate encouraging efficacy and drug tolerance with ON 01910.Na treatment of higher risk MDS patients.
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http://dx.doi.org/10.1016/j.leukres.2011.08.022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3612532PMC
January 2012

CD4(+) T cells contribute to the remodeling of the microenvironment required for sustained tumor regression upon oncogene inactivation.

Cancer Cell 2010 Nov 28;18(5):485-98. Epub 2010 Oct 28.

Division of Oncology, Departments of Medicine, Pathology and Molecular Imaging, Stanford University School of Medicine, Stanford, CA 94305, USA.

Oncogene addiction is thought to occur cell autonomously. Immune effectors are implicated in the initiation and restraint of tumorigenesis, but their role in oncogene inactivation-mediated tumor regression is unclear. Here, we show that an intact immune system, specifically CD4(+) T cells, is required for the induction of cellular senescence, shutdown of angiogenesis, and chemokine expression resulting in sustained tumor regression upon inactivation of the MYC or BCR-ABL oncogenes in mouse models of T cell acute lymphoblastic lymphoma and pro-B cell leukemia, respectively. Moreover, immune effectors knocked out for thrombospondins failed to induce sustained tumor regression. Hence, CD4(+) T cells are required for the remodeling of the tumor microenvironment through the expression of chemokines, such as thrombospondins, in order to elicit oncogene addiction.
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http://dx.doi.org/10.1016/j.ccr.2010.10.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2991103PMC
November 2010

Definition of an enhanced immune cell therapy in mice that can target stem-like lymphoma cells.

Cancer Res 2010 Dec 8;70(23):9837-45. Epub 2010 Oct 8.

Department of Pediatrics, Stanford University, Stanford, California, USA.

Current treatments of high-grade lymphoma often have curative potential, but unfortunately many patients relapse and develop therapeutic resistance. Thus, there remains a need for novel therapeutics that can target the residual cancer cells whose phenotypes are distinct from the bulk tumor and that are capable of reforming tumors from very few cells. Oncolytic viruses offer an approach to destroy tumors by multiple mechanisms, but they cannot effectively reach residual disease or micrometastases, especially within the lymphatic system. To address these limitations, we have generated immune cells infected with oncolytic viruses as a therapeutic strategy that can combine effective cellular delivery with synergistic tumor killing. In this study, we tested this approach against minimal disease states of lymphomas characterized by the persistence of cancer cells that display stem cell-like properties and resistance to conventional therapies. We found that the immune cells were capable of trafficking to and targeting residual cancer cells. The combination biotherapy used prevented relapse by creating a long-term, disease-free state, with acquired immunity to the tumor functioning as an essential mediator of this effect. Immune components necessary for this acquired immunity were identified. We further demonstrated that the dual biotherapy could be applied before or after conventional therapy. Our approach offers a potentially powerful new way to clear residual cancer cells, showing how restoring immune surveillance is critical for maintenance of a disease-free state.
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http://dx.doi.org/10.1158/0008-5472.CAN-10-2650DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2999648PMC
December 2010

Nanofluidic proteomic assay for serial analysis of oncoprotein activation in clinical specimens.

Nat Med 2009 May 12;15(5):566-71. Epub 2009 Apr 12.

Stanford University, Departments of Medicine and Pathology, California, USA.

Current methods of protein detection are insensitive to detecting subtle changes in oncoprotein activation that underlie key cancer signaling processes. The requirement for large numbers of cells precludes serial tumor sampling for assessing a response to therapeutics. Therefore, we have developed a nanofluidic proteomic immunoassay (NIA) to quantify total and low-abundance protein isoforms in nanoliter volumes. Our method can quantify amounts of MYC oncoprotein and B cell lymphoma protein-2 (BCL2) in Burkitt's and follicular lymphoma; identify changes in activation of extracellular signal-related kinases-1 (ERK1) and ERK2, mitogen-activated kinase-1 (MEK), signal transducer and activator of transcription protein-3 (STAT3) and STAT5, c-Jun N-terminal kinase (JNK) and caspase-3 in imatinib-treated chronic myelogeneous leukemia (CML) cells; measure an unanticipated change in the phosphorylation of an ERK2 isomer in individuals with CML who responded to imatinib; and detect a decrease in STAT3 and STAT5 phosphorylation in individuals with lymphoma who were treated with atorvastatin. Therefore, we have described a new and highly sensitive method for determining oncoprotein expression and phosphorylation in clinical specimens for the development of new therapeutics for cancer.
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http://dx.doi.org/10.1038/nm.1903DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4006986PMC
May 2009

Apoptosis-stimulating protein of p53 (ASPP2) heterozygous mice are tumor-prone and have attenuated cellular damage-response thresholds.

Proc Natl Acad Sci U S A 2009 Mar 26;106(11):4390-5. Epub 2009 Feb 26.

Department of Medicine, Division of Hematology and Medical Oncology, Oregon Health and Science University, Portland, OR 97239, USA.

The expression of ASPP2 (53BP2L), a proapoptotic member of a family of p53-binding proteins, is frequently suppressed in many human cancers. Accumulating evidence suggests that ASPP2 inhibits tumor growth; however, the mechanisms by which ASPP2 suppresses tumor formation remain to be clarified. To study this, we targeted the ASPP2 allele in a mouse by replacing exons 10-17 with a neoR gene. ASPP2(-/-) mice were not viable because of an early embryonic lethal event. Although ASPP2(+/-) mice appeared developmentally normal, they displayed an increased incidence of a variety of spontaneous tumors as they aged. Moreover, gamma-irradiated 6-week-old ASPP2(+/-) mice developed an increased incidence of high-grade T cell lymphomas of thymic origin compared with ASPP2(+/+) mice. Primary thymocytes derived from ASPP2(+/-) mice exhibited an attenuated apoptotic response to gamma-irradiation compared with ASPP2(+/+) thymocytes. Additionally, ASPP2(+/-) primary mouse embryonic fibroblasts demonstrated a defective G(0)/G(1) cell cycle checkpoint after gamma-irradiation. Our results demonstrate that ASPP2 is a haploinsufficient tumor suppressor and, importantly, open new avenues for investigation into the mechanisms by which disruption of ASPP2 pathways could play a role in tumorigenesis and response to therapy.
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http://dx.doi.org/10.1073/pnas.0809080106DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2657427PMC
March 2009