Michael Evans' Lab

Translational research at the interface of chemical biology and nuclear medicine

The scientific premise of the Evans lab is that there are natural, and largely untapped synergies between chemical biology and nuclear medicine.  For instance, molecular profiling technologies developed, refined, and applied by chemical biologists (e.g. proteomics, metabolomics) routinely glean biological discoveries that can be exploited by the nuclear medicine community to improve the detection and treatment of major public health challenges.  Conversely, researchers in nuclear medicine have the expertise to render new biological discoveries into translational tools for quantititively studying biology in humans with nuclear imaging (e.g. PET, SPECT) and treating disease with therapeutic radioisotopes.  In the Evans lab, we aim to breach this gap between chemical biology and nuclear medicine. 

Research in the Evans laboratory is focused on new biomarker discovery and development for nuclear imaging and therapeutic applications, primarily in oncology.  We are a lab of chemical biologists that interact closely with a diverse set of collaborators, including radiochemists, biomedical engineers, radiologists, and medical oncologists, to develop and translate into humans new imaging tools and therapies.  Training opportunities in the lab are by nature interdisciplinary, and we recruit talented young scientists from a wide variety of disciplines to meet the special challenges embedded within the field of biomarker development.  Our lab is located on the 5th floor of Genentech Hall on the Mission Bay campus of UCSF, a vibrant academic community in close proximity to several close collaborators (e.g. Professors Jim Wells, Charly Craik, Adam Renslo).  Please continue to read below for several examples of projects at the interface of chemical biology and nuclear medicine.

News

June 2020:  Dr. Evans receives the Distinguished Investigator Award from the Academy for Radiology and Biomedical Imaging Research.

June 2020: The Evans lab was awarded an Idea Expansion Award from the CDMRP Prostate Cancer Research Program to study glucocorticoid receptor expression in prostate cancer patients with 11C-YJH08, a novel radioligand developed in the lab.

April 2020:  "A novel radioligand reveals tissue specific pharmacological modulation of glucocorticoid receptor expression with positron emission tomography" is now online at ACS Chemical Biology.  Congratulations to first author Yangjie Huang!

April 2020: "Theranostic targeting of CUB domain containing protein 1 (CDCP1) in pancreatic cancer" is now online at Clinical Cancer Research.  Congratulations to first author Anna Moroz!

March 2020: A recent paper published in Molecular and Cellular Proteomics outlining how mTORC1 remodels the cell surfaceome was highlighted in ASBMB Today.  Congratulations to first authors Junnian Wei (Evans lab) an Kevin Leung (Wells lab).

December 2019:  The Evans lab was awarded a new grant from the LAM Foundation to study iron dysregulation with PET in patients.  This is on of the few human PET trials currently accruing in the world for LAM patients, and aims to better detect this multisystem disease with a radiotracer targeting ferric iron uptake through the transferrin receptor.   This project is a collaboration with Professor Steven Ruoss, MD of Stanford University.

January 2019: The article "Imaging PD-L1 expression with immunoPET" was recognized by the American Chemical Society as one of the top five most read articles in Bioconjugate Chemistry."

January 2018: "Imaging PD-L1 expression with immunoPET" is the most downloaded article within the past 30 days on the website for Bioconjugate Chemistry, and the article is featured on the cover of the January 2018 edition of BC (see above).

January 2018: An manuscript in eLife describing our recent collaboration with the Wells lab at USCF is now online (https://elifesciences.org/articles/31098).  This exciting research applied proteomics to define new actionable cell surface drug targets to treat and specifically detect in vivo with PET cancer cells with hyperactive KRAS.  This work has been highlighted by several news outlets: 

http://ecancer.org/news/13218-new-approach-attacks--undruggable--cancers-from-the-outside-in.php

https://www.technologynetworks.com/genomics/news/attacking-undruggable-cancers-from-the-outside-in-296666

https://www.news-medical.net/news/20180124/UCSF-researchers-find-new-way-to-attack-common-drivers-of-undruggable-cancers.aspx    

December 2017: "Real time transferrin based PET detects MYC positive prostate cancer" was selected by the editors of Molecular Cancer Research as a part of the "Must Read Collection" for 2017.  The article will be featured at the 2018 AACR national meeting.

November 2017:  The Evans lab was awarded a R01 from the National Institute of Mental Health to develop a new fluorine-18 labeled radioligand to measure glucocorticoid receptor expression in CNS disorders.  The three year grant will culminate in a first in human trial at UCSF!

November 2017: The Evans lab was awarded a Research grant from the Tuberous Sclerosis Alliance to apply proteomics to discover new biomarkers to better image and treat clinically problematic tumors arising from the childhood disorder tuberous sclerosis complex.

September 2017: Research from the Evans lab to develop imaging biomarkers for PET to measure MYC signaling non-invasively in human tumors was featured on the Congressionally Directed Medical Research Program website: http://cdmrp.army.mil/pcrp/research_highlights/17evans_highlight

Prostate Cancer PET Biopsies: Painless Precision Medicine

June 2017: Dr. Michael Evans' lab received an American Brain Tumor Association Discovery Award to continue studying 68Ga-citrate PET/MR in patients with high grade glioma.  The aim of this project is to improve the detection of high grade glioma by measuring mTORC1 signaling in the tumor with 68Ga, a Fe(III) biomimetic that targets the transferrin receptor on tumor cells.

April 2017: Congratulations to former undergraduate researcher Sophie Shen (UC Berkeley) for being accepted into a summer research fellowship at FibroGen, Inc., a bay area biotech company.

April 2017: Congratulations to former undergraduate researcher and technician Loc Huynh for his admission into the PhD program in the Department of Chemistry at University of Florida, as well as receiving the Grinter Fellowship to supplement his stipend.

April 2017:  Dr. Michael Evans' lab received an American Cancer Society Research Scholar Award to continue studying 89Zr-labeled transferrin, a radiotracer for PET that measures mTORC1 signaling in tumor cells non-invasively with PET.

January 2017:  Congratulations to Dr. Matthew Parker for receiving a postdoctoral fellowship from the Department of Defense Prostate Cancer Research Program.  His grant is titled "A Novel Prodrug Strategy to Treat Prostate Cancer by Targeting MYC-Driven Nucleotide Biosynthesis".  Dr. Parker is also co-mentored by Professor Davide Ruggero at UCSF.

January 2017:  Research from the Evans lab was recognized as the Featured Translational Article in the current issue of the Journal of Nuclear Medicine.  http://jnm.snmjournals.org/content/58/1/81

December 2016:  Congratulations to Dr. Charles Truillet on accepting a Professorship in the Department of Biomedical Imaging at the French Alternative Energies and Atomic Energy Commission (CEA).

January 2016:  Congratulations to Dr. Charles Truillet for receiving a postdoctoral fellowship from the Department of Defense Prostate Cancer Research Program.  His grant is titled "Development of radiolabeled transferrin constructs to detect and treat castration resistant prostate cancer".  Dr. Truillet is also co-mentored by Dr. Davide Ruggero of UCSF.

Evans lab article recognized as "Editor's Choice" in Molecular Pharmaceutics - American Chemical Society

2015 SNMMI Highlioghts Lecture, Part 1

Non-Invasive Biomarkers For Prostate Cancer

New Imaging Agent Could Improve Prostate Cancer Diagnosis and Treatment

Transferrin PET Project

Opportunities

Post-doctoral Opportunities

The Evans lab is currently seeking exceptional candidates for a postdoctoral appointment focusing on new probe development for nuclear theranostics and studying tumor immunology.

Interested candidates should contact Dr. Evans directly and provide a copy of their CV and references at [email protected].

Graduate Students

Dr. Evans is a member of the Chemistry and Chemical Biology graduate program (https://ccb.ucsf.edu/) and the Pharmaceutical Sciences and Pharmacogenomics graduate program (https://pspg.ucsf.edu/) at UCSF.  The lab is openly accepting students. Students interested in rotations should contact Dr. Evans directly via email.  

Staff

Employment Opportunities for staff positions are posted through the UCSF employment websites

Publications

Evans Lab Journal of Nuclear Medicine cover

Examples of cover art from Evans lab publications.  A complete list of Evans lab publications can be found at Michael Evans' UCSF profiles page.

People

Michael J. Evans, PhD, Evans LabMichael J. Evans, PhD, is an Assistant Professor in Residence in the Department of Radiology and Biomedical Imaging at the University of California, San Francisco. He is an experienced chemical biologist with a focus on molecular imaging, organic chemistry, and biomarker discovery through proteomics. Dr. Evans obtained his PhD in Organic Chemistry from The Scripps Research Institute in La Jolla, California under the supervision of Professor Benjamin Cravatt, followed by postdoctoral fellowship in Molecular Imaging at Memorial Sloan Kettering Cancer Center in New York under the supervision of Professors Charles Sawyers and Jason Lewis. He is the co-author of over 40 publications in peer-reviewed journals like Nature Medicine, eLife, Clinical Cancer Research, and PNAS.  Dr. Evans has received several awards, including a 2013 Young Investigator Award from the Prostate Cancer Foundation, a Pathway to Independence award (K99/R00) from the National Cancer Institute, three Idea Development Awards from the Department of Defense, and a Research Scholar Award from the American Cancer Society.  He was also a scientific co-founder of ORIC Pharmaceuticals, Inc., a bay area biotechnology company dedicated to defining new therapies for treatment refractory cancers.  Dr. Evans is a member of the Chemistry and Chemical Biology graduate program, an adjunct member of the Department of Pharmaceutical Chemistry (https://pharmchem.ucsf.edu/), and a full member of the Helen Diller Family Cancer Center.


Junnian Wei, PhD, Evans LabJunnian Wei, PhD, is a Postdoctoral Fellow in the Evans laboratory. He received his BSc, MSc and PhD in Chemistry from Peking University, China under the supervision of Professor Zhenfeng Xi. After a brief postdoctoral fellowship at the University of California, Los Angeles in Professor Paula Diaconescu group, he joined the Evans lab to study proteomics, radiochemistry, and experimental therapeutics. He is an organometallic chemist with additional experience in organic synthesis, polymer chemistry and DFT calculations.   Dr. Wei is the first or co-author on nearly 20 manuscripts in well respected peer reviewed journals like Journal of American Chemical Society and Angewandte Chemie. He was also the recipient of the National Scholarship for Graduate Students in Chemistry from the Ministry of education of China.


Yung-Hua Wang, Evans LabYung-Hua Wang is a Staff Research Associate, and the Evans lab manager.  He received a B.S. in Chemistry from the University of California, Berkeley, and was an undergraduate researcher in the Evans lab for two semesters prior to joining the lab full-time.  Mr. Wang is a co-author on a manuscript in Bioconjugate Chemistry, and works on several small molecule synthesis projects as well as the preclinical assessment of new radiotracers.


Yangjie Huang, PhD, Evans LabYangjie Huang, PhD, is a Postdoctoral Fellow in the Evans laboratory. He received his BSc (2012) in Chemistry from Guangxi University of China, and PhD (2017) in the college of chemistry at the Fuzhou University of China under the supervision of Professor Zhiqiang Weng. He is an experienced organic chemist and good at organic synthesis, organofluorine chemistry and organometallic complex. Dr. Huang is the first or co-author on nearly 15 manuscripts in well respected peer reviewed journals like Angewandte Chemie and Organic Letters. He joins the Evans lab to study radiochemistry and molecular imaging.


Ning Zhao, PhD, Evans labNing Zhao, PhD received his BSc (2010) in Chemistry from Lanzhou University, China and a Ph.D. (2016) in Organic Chemistry from Louisiana State University under the supervision of Professors Dr. Graca Vicente and Dr. Kevin Smith.  Dr. Zhao is an experienced organic chemist with experience in the development of new chemistry for functionalizing fluorescent dyes and carborane clusters for coupling to bioactive molecules.  He is the first or co-author on more than 10 publications in well-respected peer-reviewed journals like the Journal of Organic Chemistry, Bioconjugate Chemistry, and Chemistry – a European Journal. 


Zhuo Chen, Ph.D., Zhuo Chen, PhD is a Postdoctoral Fellow in the Evans lab. She earned her B.S. in Materials Chemistry from Tianjin University, China, and a M.S. in Chemistry (specializing in polymer science) from the University of Massachusetts Lowell, MA. In 2018, she received her Ph.D. in Chemistry under the supervision of Professor Jeremiah Gassensmith at the University of Texas at Dallas, where she focused on functionalizing virus-like particles as a platform for stimuli-responsive drug delivery and fluorescence imaging. She is a co-author on 8 manuscripts in well-respected peer reviewed journals like Small, Bioconjugate Chemistry, and Chemical Communications.  She has extensive experience in nanoparticle-based therapeutics development and formulation, bioconjugation chemistry and organic synthesis.


Shalini Chopra, PhD is a postdoctoral fellow in the Evans lab.  She received her B.Sc. (Hons. School) in Biophysics and M.Sc. in Nuclear Medicine from Panjab University, India.  She received her Ph.D. in Biophysics from Panjab University under the supervision of Dr. Baljinder Singh, Professor at PGIMER, India.  Her Ph.D. project involved development of antimicrobial peptide fragments as potential PET probes for imaging bacterial infections in murine models.  She received the DAAD (German Academic Exchange Service) fellowship to carry a part of thesis work under the stewardship of Professor Hans-Jürgen Wester at Technical University of Munich, Germany.  She is well versed with the molecular imaging techniques (pre-clinical and clinical level), radiolabeling and conjugation strategies for the development of new tracers, and has authored publications in Applied Radiation and Isotopes and Cancer Biotherapies and Radiopharmaceuticals.


Nima HooshdaranNima Hooshdaran, is a staff research associate in the Evans Lab. He got his B.S. from UCLA in microbiology, immunology and molecular genetics. During that time he studied miRNAs and their roles in stem cell differentiation under Dr. Zamudio. He continued after graduation as a lab manager in Dr. Zamudio’s lab and has publications in Molecular Cell & Cell reports from his research. 
 


Nicole Nagayama is a second year undergraduate student at Saint Mary’s College of California majoring in Biology. She volunteers at UCSF Benioff Children's Hospital as well as works as a gymnastics coach. After completing her undergraduate degree she plans to attend medical school.

 


Alumni

Ashwin NagarajAshwin Nagaraj was a student in the Masters in Biomedical Imaging Program in the Department of Radiology and Biomedical Imgaing at UCSF.  He received his BS in Molecular and Cell Biology at the University of Connecticut.  His research in the Evans lab interrogated the relationship between mTORC1 signaling and iron metabolism in human disease.  He is currently studying to become a Doctor of Osteopathic Medicine at Kansas City University of Biomedical Sciences.


Mariaelena NaborsMariaelena Nabors was a student researcher in the Summer Research Training Program at UCSF.  Her research in the Evans lab focused on understanding how oncogenic drivers of glioma remodel the surface-ome.  She is currently a first year graduate student in the Biomedical and Biological Sciences PhD program at University of North Carolina Chapel Hill.

 


Jeffrey HsiaoJeffrey C. Hsiao  was a student in the Masters in Biomedical Imaging (MSBI) program in the Department of Radiology and Biomedical Imaging at UCSF.  He received his BS in Molecular, Cell, Developmental Biology from University of California Los Angeles in 2016.  His prior research in the lab of Professor Aldons Lusis investigated biomarkers in heart failure models using a systems genetics approach. Jeff is now attending the Pharmacology PhD program at Weill Cornell Medical College in New York.


Julia Lee, Evans LabJulia Lee was an undergraduate student at UC Berkeley majoring in chemistry with a minor in toxicology. She will be assisting with the molecular characterization of new PET radiotracers for cancer imaging in the Evans Lab.  Julia is now a PharmD student at the UCSF School of Pharmacy.

 


Anna Pavlova-Moroz, MD, Evans labAnna Pavlova-Moroz, MD is a visiting scholar in the Evans laboratory.  She successfully graduated from I.M. Sechenov First Moscow State Medical University summa cum laude in Internal Medicine, followed by a residency in Hematology-Oncology in the Department of Chemotherapy and Bone Marrow Transplantation in Russian National Research Center for Hematology.  She is currently a PhD student at Skolkovo Institute of Science and Technology (Skoltech) majoring in Biomedical Science, and the author of several scientific papers and abstracts. Anna is currently a Research Associate Scientist in the Department of Bone Marrow Transplantation at Stanford University.


Suzanna Tom, Evans Lab

Suzanna Tom is a third year undergraduate majoring in Chemical Biology at UC Berkeley. She will be studying the pharmacology of new radiotracers for prostate cancer imaging.

 

 


Charles Truillet, PhD, Evans LabCharles Truillet, PhD was a Postdoctoral Scholar in the Evans laboratory. He was the recipient of a postdoctoral fellowship from the Department of Defense's Prostate Cancer Research Program. His postdoctoral work was focused on identifying and exploiting for diagnostics and therapy new biomarkers regulated by central oncogenes, including the use of transferrin to measure mTORC1 activity, and the first demonstration in humans that PSMA targeted PET can be used to visualize androgen receptor inhibition in prostate cancer metastases.  During his two year appointment as a postdoctoral fellow, he was a co-author on seven articles (three first author) in well respected peer reviewed journals like Journal of Nuclear Medicine, Clinical Cancer Research, and Molecular Pharmaceutics.  He is currently a Professor with tenure in the Department of Biomedical Imaging at the French Alternative Energies and Atomic Energy Commission (CEA).


Christopher Drake, PhD, Evans LabChristopher R. Drake, PhD, was an Associate Specialist in the Evans lab.  During his appointment, Dr. Drake developed a novel, enzyme catalyzed, site specific radiofluorination strategy for small biomolecules.  This work was disclosed in ACS Chemical Biology.  Dr. Drake is currently a senior radiochemist at Sofie Biosciences, Culver City, CA.
 


Leila Ranis, MS, Evans LabLeila Ranis, MS, was a Junior Specialist in the Evans lab.   Ms. Ranis received a Bachelor of Science in Chemical Biology from the University of California, Berkeley. She earned a Master of Science from the University of Notre Dame under the supervision of Professor Seth Brown. Her master's thesis focused on the synthesis and reactivity studies of group VI metal complexes, and their applications to green chemistry and renewable energy storage. She is the first author of a manuscript in Inorganic Chemistry. She is a currently a medicinal chemist at BioRad Laboratories, Hercules CA.


Khaled Jami, Evans LabKhaled Jami was an undergraduate volunteer and Staff Research Associate in the Evans lab.  He worked on several small molecule synthesis projects while in the lab. He recently earned his B.S. in Chemistry from University of California Berkeley, and is now currently a staff scientist at ThermoFisher, Inc. in the Los Angeles area. He is currently a PhD student in the Chemistry program at University of California Davis.


Matthew Parker, PhD, Evans LabMatthew Parker, PhD was a Postdoctoral Fellow in the Evans lab.  He is the recipient of a 2016 Department of Defense Prostate Cancer Research Program postdoctoral fellowship.  He received his BSc and MSc in Chemistry from Binghamton University (NY), and his PhD in Chemistry from the University of Pittsburgh under the supervision of Professor Christian Schafmeister.  He is an experienced organic and radiochemist, with five manuscripts published in well respected peer reviewed journals like Journal of the America Chemical Society, Journal of Physical Chemistry A, and Clinical Cancer Research. He was also the recipient of the C. Max Hull Award in Organic Chemistry from Binghamton University, the Lois B. Mackey Award from the University of Pittsburgh, and two poster awards from the American Chemical Society.


Loc Huynh, Evans labLoc Huynh was a Staff Research Associate in the Evans lab.  He received a B.S. degree in Chemistry from the University of California, Berkeley. Mr. Huynh is an experience organic chemist with strong skills in the preclinical assessment of novel small molecule and antibody based radiotracers. He is an author of two manuscripts in Clinical Cancer Research and Molecular Pharmaceutics.  He is currently a PhD candidate in the Department of Chemistry at the University of Florida. 


Sophie Shen, Evans lab

Sophie Shen is currently enrolled in the PharmD program at UCSF.  She previously conducted a work study program in the Evans lab focused on the preclinical evaluation of the pharmacology of new radiotracers.  Sophie is now a PharmD student at the UCSF School of Pharmacy..

 

 


Nhan Dang, Evans LabNhan Dang is a second year undergraduate student at UC Berkeley majoring in Chemistry.  He joined the Evans in Spring 2017 to study radiotracer development in cancer models. 

 

 


Lisa Wu, PhD was an Associate Specialist in the Evans lab.  She is now an Instructor in the Department of Chemistry, San Francisco State University.

Funding

The Evans lab graciously accepts financial support from the following sources:

Funding Sources for Evans Lab

Research Directions

Applying cell surface proteomics and antibody engineering to develop new technologies for cancer "theranostics"

The nuclear theranostic concept, in which a radiotracer is prospectively applied to identify with imaging those cancer patients that have sufficient protein target expression to respond to a mechanistically related radiopharmaceutical, is now in widespread clinical practice with the recent FDA approvals of Lutathera and Azedra for endoradiotherapy.  These milestones, combined with recent advances in the use of alpha emitting radioisotopes (e.g. Ac-225, Th-227) for endoradiotherapy, create an urgent unmet need to apply discovery biology approaches to identify and exploit new protein targets for cancer theranostics. 

In collaboration with the Wells lab at UCSF (https://wellslab.ucsf.edu/), we are addressing thsi unmet need by applying proteomics to identify proteins on the cancer cell surface that are strongly induced by undruggable oncogenes (e.g. RAS, transcription factors).  Because we are focusing on the surface-ome, antibodies can be rapidly evolved through phage display to bind highly upregulated proteins, and of course functionalized with radioisotopes for imaging or endoradiotherapy. 

Following on a recent manuscript describing how mutant KRAS remodels the cancer cell surface-ome, we have shown for the first time that antibodies targeting the ectodomain of CUB domain containing protein 1 can be labeled with radioisotopes to visualize (e.g. Zr-89) and treat (Lu-177, Ac-225) RAS driven cancers.  CDCP1 is broadly upregulated in cancer, so the technologies and proof of concept treatment data may have therapeutic applications beyond RAS driven cancers.

Moving forward, we are continuing to collaborate closely with the Wells lab to develop several new proteomics data sets to identify cell surface proteins uprregulated by other "undruggable" or poorly druggable oncogenic drivers of cancer.  For example, we recently disclosed how mTORC1 activity remodels the cell surface-ome, which may lead to more ablative therapeutic strategies compared to treatment with cytostatic rapalogues.

Relevant publications:

Martinko AJ, Truillet C, Julien O, Diaz JE, Horlbeck MA, Whiteley G, Blonder J, Weissman JS, Bandyopadhyay S, Evans MJ, Wells JA. Targeting RAS-driven human cancer cells with antibodies to upregulated and essential cell-surface proteins. Elife. 2018 01 23; 7. PMID: 29359686.

Moroz A, Wang YH, Sharib JM, Wei J, Zhao N, Huang Y, Chen Z, Martinko AJ, Zhou J, Lim SA, Zhang LH, Seo Y, Carlin S, Leung KK, Collisson EA, Kirkwood KS, Wells JA, Evans MJ. Theranostic targeting of CUB domain containing protein 1 (CDCP1) in pancreatic cancer. Clin Cancer Res. 2020 Apr 27. PMID: 32341034.

Wei J, Leung K, Truillet C, Ruggero D, Wells JA, Evans MJ. Profiling the Surfaceome Identifies Therapeutic Targets for Cells with Hyperactive mTORC1 Signaling. Mol Cell Proteomics. 2020 02; 19(2):294-307. PMID: 31792071.

 

Measuring androgen receptor signaling in human prostate cancer tumors with PET

Although two potent inhibitors of the androgen receptor (Enzalutamide, Abiraterone) were recently shown to improve overall survival in men with castration resistant prostate cancer, responses are only observed in 50% of patients for about a year.  One explanation for these observations is that we may be “under-dosing” the androgen receptor with the current standard of care doses, and incomplete inhibition of the drug target may lead to poor initial responses or encourage adaptive resistance.  Since we currently have no tools to monitor changes in androgen receptor biology post therapy, my collaborators and I developed a panel of imaging biomarkers to measure androgen receptor biology with positron emission tomography.

Because the androgen receptor is a transcription factor, we mined the AR transcriptome to identify "imageable" AR target genes.  We identified numerous cell surface or secreted antigens against which potent and selective antibodies had been raised.  After coupling the antibodies to radionuclides like copper-64 and zirconium-89, we conducted small animal imaging studies to verify whether cell surface changes in antigen expression levels could bve quantifed wi

th PET, and whether the changes correlated with alterations in intracellular AR signaling levels.  In all cases, the ability to measure post therapy (enzalutamide or orchiectomy) changes in AR activity was visually obvious on the PET scans, and because two of the three radiotracers are already in patients with castration resistant prostate cancer, the opportunity to test the impact of drug dose on patient response was imminent.  These data were published in three manuscripts at PNAS, Cancer Discovery, and the Journal of Nuclear Medicine.

The first human trial at UCSF testing the relationship between AR signaling and PSMA expression:

We have since begun the first human trial at UCSF to test whether PSMA expression is increased in prostate cancer lesions after treatment with androgen deprivation therapy (AR inhibition).  In collaboration with Professors Thomas Hope, Rahul Aggarwal, and Eric Small, we have shown that a PSMA targeted PET scan dramatically intensifies four weeks after the initiation of ADT, consistent with the animal data.  A larger clinical trial

 will be requried to assess the breadth of this "PSMA flair" in humans, and we are actively pursuing this.  These data were recenty published in the Journal of Nuclear Medicine.  These results provide the foundation for testing PSMA PET as a pharmacodynamic biomarker for antiandrogens in patients with castration resistant prostate cancer (CRPC).  Moreover, based on our work, several groups are now evaluating the therapeutic efficacy of combined antiandrogen therapy with PSMA-targeted drug conjugates in patients with CRPC.

Developing new radioligands to measure glucocorticoid receptor expression with PET

The glucocorticoid receptor is a master regulator of normal physiology and its dysregulation is thought to drive the pathophysiology of many diseases, including mood disorders, metabolic diseases, and even cancer.  Cell and genetically engineered animal models have been the mainstays for carefully articulating the abovementioned features of GR (patho)biology.  Fully understanding GR’s role in human physiology and disease, as well as developing next generation therapeutics to more selectively modulate GR, requires new technologies that can safely probe GR signaling in living subjects.  The lack of non-invasive biomarkers to interrogate GR signaling in humans has left the field to perform very suboptimal assays, for instance, analysis of GR and target gene expression levels from tissues collected at autopsy.

To better interrogate GR signaling dynamics in humans, we have developed a library of radiolabeled corticosteroids and synthetic agonists to measure GR expression levels in vivo. These tools have enabled an unprecedented view of GR expression dynamics to reveal aspects of GR biology that are only occurring in vivo.  Moreover, we have demonstrated that GR PET can be used to reveal unexpected tissue specific drug-GR interactions, which establishes an entirely new paradigm for the development of selective GR modulators-a major unmet clinical need.  Lastly, I supervise an ongoing clinical trial to translate one radioligand, 11C-YJH08, into humans to make the first non-invasive measurements of GR expression levels in healthy subjects and patients with mood disorders or prostate cancer.  

Relevant Publications:

Huang Y, Zhao N, Wang YH, Truillet C, Wei J, Blecha JE, VanBrocklin HF, Seo Y, Sayeed M, Feldman BJ, Aggarwal R, Behr SC, Shao H, Wilson DM, Villanueva-Meyer JE, Gestwicki JE, Evans MJ. A novel radioligand reveals tissue specific pharmacological modulation of glucocorticoid receptor expression with positron emission tomography. ACS Chem Biol. 2020 Apr 07. PMID: 32255605.

Truillet C, Parker MFL, Huynh LT, Wei J, Jami KM, Wang YH, Shen YS, Sriram R, Wilson DM, Kurhanewicz J, Evans MJ. Measuring glucocorticoid receptor expression in vivo with PET. Oncotarget. 2018 Apr 17; 9(29):20399-20408. PMID: 29755660.

 

Ferronostics: new technology development to measure iron dyshomeostasis with PET to identify diseases susceptible to therapies targeting iron 

We have developed new technologies to image iron with positron emission tomography (PET) in an oxidation state specific fashion and conducted radiomic studies in animals and humans to better understand how to exploit iron dyshomeostasis for the detection or treatment of human diseases.  We are recognized for the discovery that mTORC1 and/or MYC are primary drivers of cellular uptake of ferric iron via transferrin in tumors and neoplastic disorders like LAM.  Achieving this in mice was enable by new technology development (e.g. 89Zr-labeled transferrin) to measure ferric iron deposition in the most clinically relevant animal models (e.g. GEMMs, PDX’s).  I have also led seven clinical trials in patients with cancer or LAM studying ferric iron uptake using 68Ga-citrate PET (68Ga is a ferric iron biomimetic in vivo).  Radiomic studies have shown that MYC and/or mTORC1 hyperactivity are the primary drivers of ferric iron uptake, a finding that has since motivated us to test if disorders bearing mutations in these pathways are susceptible to therapies that deplete or further exacerbate iron dyshomeostasis to promote “ferroptosis”.  To further enable these studies, we recently developed the first chemical sensor (18F-TRX) to detect the cytosolic pool of bioactive ferrous iron (the so called “labile iron pool”) with PET.  This radiotracer has enabled unprecedented measurements of cellular LIP in living subjects, which is essential to our understanding of iron regulation as LIP cannot be measured with conventional analytical techniques that require disrupting the native cellular environment (e.g. ICP-MS).  Monitoring LIP in vivo with PET will help us predict if LIP concentration is sufficiently augmented to target therapeutically, or if treatments designed to induce ferroptosis are efficacious.  In summary, my lab is internationally recognized as a leader in the development of theranostic strategies to target iron dyshomeostasis.

Relevant Publications

Holland JP, Evans MJ, Rice SL, Wongvipat J, Sawyers CL, Lewis JS. Annotating MYC status with 89Zr-transferrin imaging. Nat Med. 2012 Oct; 18(10):1586-91. PMID: 23001181.
 
Evans MJ, Holland JP, Rice SL, Doran MG, Cheal SM, Campos C, Carlin SD, Mellinghoff IK, Sawyers CL, Lewis JS. Imaging tumor burden in the brain with 89Zr-transferrin. J Nucl Med. 2013 Jan; 54(1):90-5. PMID: 23236019.
 
Doran MG, Carnazza KE, Steckler JM, Spratt DE, Truillet C, Wongvipat J, Sawyers CL, Lewis JS, Evans MJ. Applying 8?Zr-Transferrin To Study the Pharmacology of Inhibitors to BET Bromodomain Containing Proteins. Mol Pharm. 2016 Feb 01; 13(2):683-8. PMID: 26725682.
 
Behr SC, Aggarwal R, Seo Y, Aparici CM, Chang E, Gao KT, Tao DH, Small EJ, Evans MJ. A Feasibility Study Showing [68Ga]Citrate PET Detects Prostate Cancer. Mol Imaging Biol. 2016 12; 18(6):946-951. PMID: 27184068.
 
Truillet C, Cunningham JT, Parker MFL, Huynh LT, Conn CS, Ruggero D, Lewis JS, Evans MJ. Noninvasive Measurement of mTORC1 Signaling with 89Zr-Transferrin. Clin Cancer Res. 2017 Jun 15; 23(12):3045-3052. PMID: 28007777.
 
Mari Aparici C, Behr SC, Seo Y, Kelley RK, Corvera C, Gao KT, Aggarwal R, Evans MJ. Imaging Hepatocellular Carcinoma With 68Ga-Citrate PET: First Clinical Experience. Mol Imaging. 2017 Jan-Dec; 16:1536012117723256. PMID: 28893116.
 
Aggarwal R, Behr SC, Paris PL, Truillet C, Parker MFL, Huynh LT, Wei J, Hann B, Youngren J, Huang J, Premasekharan G, Ranatunga N, Chang E, Gao KT, Ryan CJ, Small EJ, Evans MJ. Real-Time Transferrin-Based PET Detects MYC-Positive Prostate Cancer. Mol Cancer Res. 2017 09; 15(9):1221-1229. PMID: 28592703.
 
Behr SC, Villanueva-Meyer JE, Li Y, Wang YH, Wei J, Moroz A, Lee JK, Hsiao JC, Gao KT, Ma W, Cha S, Wilson DM, Seo Y, Nelson SJ, Chang SM, Evans MJ. Targeting iron metabolism in high-grade glioma with 68Ga-citrate PET/MR. JCI Insight. 2018 11 02; 3(21). PMID: 30385712.
 
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Development of a biochemically catalyzed site specific radiofluorination strategy for biomolecules

Although fluorine-18 is widely used clinically for the preparation of small molecule radiotracers, the chemistry applied is often too harsh to be used for the preparation of radiofluorinated small biomolecules (e.g. peptides, diabodies, minibodies).  As the community transitions away from imaging with large biomolecules that require several days post injection to visualize cancer lesions, to smaller biomolecules that can empower same day imaging, there is an urgent need to develop better chemistry for appending short half life radionuclides onto small biomolecules. Development of a biochemically catalyzed site specific radiofluorination strategy
In collaboration with Drs. Charles Craik and Henry VanBrocklin, we have developed a new site specific radiofluorination technology that uses the enzyme lipoic acid ligase A to append a fluorine-18 analogue of lipoic acid to an epitope engineered onto the biomolecule of interest (http://pubs.acs.org/doi/10.1021/acschembio.6b00172) .  Proof of concept chemistry using a Fab to urokinase plasminogen activator receptor (uPAR) showed the bioconjugation chemistry was very high yielding (>90%) under mild conditions and in short time periods (<15 min).  The chemistry also scales to produce large enough quantities of radiotracer for injection into small animals for PET.   We are now applying this chemistry to study other antigens of interest to cancer imaging.