Evans Lab

Imaging Biomarker Development to Foster Precision Medicine

Research in the Evans laboratory is focused on new biomarker discovery and development for nuclear imaging and medicine applications.  We interact closely with a diverse set of collaborators, including chemical biologists, radiochemists, and medical oncologists, to identify and address major unmet clinical needs for biomarker development in oncology.  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.

Opportunities

Post-doctoral Opportunities

The Evans lab is currently seeking exceptional candidates for a postdoctoral appointment focusing on immunoPET in cancer models.  Those with experience in antibody development, radiochemistry, and organic chemistry are encouraged to contact Dr. Evans directly and provide a copy of their CV and references at michael.evans@ucsf.edu.

Staff

Employment Opportunities for staff positions are posted through the UCSF Department of Human Resources

Publications

A complete list of publications can be found at Michael Evans' UCSF profiles page.

People

Michael 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 36 publications in peer-reviewed journals, several conference abstracts, and the co-inventor on three patents.  Dr. Evans was awarded the 2013 David H. Koch Young Investigator Award from the Prostate Cancer Foundation, a Pathway to Independence award from the National Cancer Institute, and an Idea Development Award from the Department of Defense Prostate Cancer Research Program.  He is also a scientific 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 Helen Diller Family Cancer Center.


 


Matthew Parker, PhD is a Postdoctoral Fellow in the Evans lab.  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.

Junnian Wei, PhD, is a Postdoctoral Fellow in the Evans laboratory. He received his BSc, MSc and PhD in Chemistry from Peking University, China (PKU) 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 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 Graduated Students in Chemistry from the Ministry of education of China.

Loc Huynh is 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.
 

Yung-Hua Wang is a Staff Research Associate in the Evans lab.  He received a B.S. in Chemistry from the University of California, Berkeley.  Mr. Wang works on several small molecule synthesis projects as well as the preclinical assessment of new radiotracers.

 

 


Alumni

Charles 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 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 radiochemist at Sofie Biosciences, Culver City, CA.

Leila 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 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 applying to PhD programs in Chemistry.

 

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.

 

Research Directions 

Biomarker discovery

In collaboration with the Wells lab at UCSF (http://wellslab.ucsf.edu/), we are currently applying shotgun proteomic technologies to identify new “imageable” biomarkers in genetically defined cancer models.  The long term goal of this project is to define a privileged list of biomarkers that might be used to identify cells harboring hyperactive signaling, distinguish aggressive from indolent clinical disease, and to monitor the pharmacodynamics effects of experimental targeted therapies in early phase clinical trials

Measuring androgen receptor activity with “imageable” target genes

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 collab

oration 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.

 

 

 

 

 

 

Measuring MYC activity with “imageable” target genes

MYC is a validated oncogenic driver of many solid tumors and hematologic malignancies.  Developing an imaging biomarker to measure MYC activity is potentially impactful clinically for a number of reasons.  First, despite a deep appreciation of the role of the transcription factor MYC in cancer initiation and progression in preclinical models (because we can study animal tissues invasively), the cancer community understands very little about the role of MYC activity in human disease.  Our limited knowledge of MYC biology in human disease is primarily due to the challenges in acquiring tissue biopsy for research purposes, especially in late stage, metastatic cancer.  Our hypothesis is that a MYC specific PET biomarker will be accepted into widespread clinical use if the radiotracer is easy and cheap to synthesize, straighforward to implement, and does not incovenience the patient.  Second, it is important to develop an imaging biomarker that measures MYC activity as many indirect inhibitors of MYC (i.e. drugs whose primary target is not MYC, but a protein that regulates of MYC activity) are now undergoing their first clinical evaluation in cancer patients.  Two prominent examples are inhibitors of cyclin dependent kinases (CDK4/6) and BET bromodomain containing proteins (BRD4).  A translational assay to measure MYC activity longitudinally would be crucial to better understand these therapies’ ability to inhibit MYC activity in man, particularly in a phase I/II dose escalation study.  Lastly, with the pending development of the first high sensitivity, whole body PET scanner at UC Davis (http://explorer.ucdavis.edu/), the field may be positioned to conduct the first studies examining the utility of low dose PET as a screening tool in high risk populations, akin to the use of low dose CT for lung cancer screening in former heavy smokers. Oncogene specific imaging probes for well established early drivers of cancer would be ideal to apply for screening to capture actively transitioning cells in high risk patients.

 

Developing transferrin-based PET as a biomarker of MYC activity:

We developed the first quantitative imaging biomarker to measure MYC activity.  Because MYC is a transcription factor, we reasoned that relative changes in the expression level of an "imageable" MYC target gene could be exploited to quantify the degree of intracellular MYC signaling.  Among the target genes most profoundly impacted by MYC activity is the transferrin receptor (TFRC).  TFRC is a direct MYC target gene and expressed predominantly at the surface of cells (rather than stored intracellularly), making it an attractive therapeutic target.  Moreover, the soluble ligand of TFRC, transferrin (Tf), has been used by the nuclear medicine community  for decades to bring radionuclides to tumors, most notably 67Ga-citrate. 

We developed 89Zr-transferrin by conjugating 89Zr to DFO chelators engineered onto lysine side chains in Tf (Holland, J.P. and Evans, M.J., et al. Nature Medicine, 2011).  89Zr-Tf is exceptionally stable in vivo, and the long half life of zirconium-89 allows for imaging several days post injection, which can improve image quality.  Our first efforts to validate 89Zr-Tf as a biomarker of MYC activity showed that the radiotracer specifically accumulated in MYC driven prostate cancer models, and genetic ablation of MYC completely suppressed radiotracer uptake in prostate cancer cells.  Moreover, using a genetically engineered mouse with MYC specific overexpression in the prostate, we were able to show that 89Zr-Tf can image prostate cancer cells with high MYC activity, as well as preneoplastic cells with high MYC activity.  This was significant, as this was the first demonstration that PET could be used to study aberrant oncogene signaling in non-transformed cells.

We have since shown that the anti-MYC effects of indirect MYC inhibitors can be quantified with 89Zr-Tf PET.  For instance, treatment of B cell lymphoma models with BRD4 inhibitors results in a suppression of 89Zr-Tf uptake in tumors that is driven by MYC inhibition (Doran, M.G. et al. Molecular Pharmaceutics, 2016).  In addition, in collaboration with Scott Lowe at MSKCC (https://www.mskcc.org/research-areas/labs/scott-lowe), we showed that the anti-MYC effects of CDK9 inhibitors in hepatocellular carcinoma could be quantified with 89Zr-Tf PET (Huang, C-H. et al. Genes and Development, 2015). Both of these studies underscore the potential role of Tf-based PET in interpreting the pharmacology of indirect MYC inhibitors, and this PET strategy may be highly useful to optimize dose in a phase I/II trial, as well as identify those likely to respond to drug earlier.

The clinical translation of 89Zr-Tf:

Professor Jason Lewis of MSKCC (https://www.mskcc.org/research-areas/labs/jason-lewis) and I received NCI support for the clinical translation of 89Zr-Tf in 2013 (R01CA176671).  We have currently completed IND enabling studies, and expect to begin first in man studies in cancer patients in 2017.  

 

Development of [68]Ga-transferrin to detect MYC driven tumors in humans

Because 89Zr-Tf is an experimental radiotracer not yet in humans, we have also opened the first human studies at UCSF to determine if 68Ga-Tf (formed in situ after intravenous administration of 68Ga-citrate) can detect castration resistant prostate cancer metastases (which can be highly MYC driven).  In collaboration with Drs. Spencer Behr, Rahul Aggarwal, and Eric Small, the first dose escalation study was conducted to determine the optimal dose of radiotracer and time post injection for imaging, which we determined to be >3.5 mCi and >3 hours post injection (Behr, S.C. and Aggarwal, R. et al. Molecular Imaging and Biology, 2016).  In the first eight patients studied, the radiotracer detected approximately 75% of lesions that were registered by bone scan and/or CT.  The appearance of true negatives was significant, as it negates the argument that 68Ga-Tf accumulation at early time points post injection is due to non-specific accumulation in regions with unusual vascularity (i.e. the enhanced permeability and retention effect).  Moreover, the degree of uptake is highly consistent with the well accepted position that MYC hyperactivity is prevalent in CRPC, but perhaps not uniformly overexpressed.  Lastly, the heterogeneity of uptake in tumors, even within the same patient, underscores the potential clinical importance of developing oncogene specific tools, as they could reveal a clinically significant layer of biological heterogeneity that cannot be easily accessed using other diagnostic techniques (e.g. biopsy, analysis of circulating tumor cells or biomarkers).

Because many of the patients are also participating in the SU2C/AACR/PCF sponsored West Coast Dream Team, we have collected biopsies for lesions that have been imaged with 68Ga-Tf.  Therefore, we can begin to verify the molecular basis of radiotracer uptake using RNA-seq and companion methodologies like array CGH.  This work is ongoing as we continue to accrue patients.  This project is currently sponsored by Prostate Cancer Foundation Young Investigator Awards (Evans, Aggarwal), and a Department of Defense Idea Development Award (Aggarwal).

Development of a biochemically catalyzed site specific radiofluorination strategy

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.  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 (Drake, C.R. et al. ACS Chemical Biology, 2016) .  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.