Steven W Millward, Ph.D.
Department of Cancer Systems Imaging, Division of Diagnostic Imaging
About Dr. Millward
Directed Evolution of Imaging Agents. The ideal molecular imaging agent would have the affinity and target specificity of monoclonal antibodies along with the rapid systemic clearance of small molecules. While peptides have shown promise as in vitro imaging probes, their short half-life, poor stability, and low affinity have traditionally made them unsuitable for in vivo applications. They are using mRNA display in conjunction with chemical modification to select for high-affinity, modification-resistant peptides in ex vivo and in vivo systems.
Visualizing Autophagy in Living Systems. Autophagy is a highly conserved catabolic process where cellular components are engulfed and degraded to provide energy in times of metabolic stress. Autophagy has been shown to play both a pro-tumor and anti-tumor role in cancer. While the molecular mechanisms of autophagy are beginning to be understood, there is no easy way to unambiguously image autophagy in living cells and tissues or to determine the extent of autophagic flux. They are using a chemical biology, metabolomics, and directed evolution strategies to visualize this and other related forms of cell death in models of ovarian cancer
Present Title & Affiliation
Associate Director of Chemistry, Department of Cancer Systems Imaging, Division of Diagnostic Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX
Graduate Faculty, Division of Graduate School of Biomedical Sciences, The University of Texas Health Science Center, Houston, TX
Molecular Imaging has enormous potential to qualitatively change the way cancer is understood, diagnosed, and treated. The advancement of this field depends greatly on the development of new imaging probes that report the biological activity of cancer-relevant proteins in addition to their absolute concentration in the tumor cell. The peptide-based caspase activity probes described in this proposal represent a new and powerful approach to this problem that can guide cancer treatment in real time. I have worked in the field of peptide discovery, chemistry, and characterization for over ten years; as a graduate student with Prof. Rich Roberts (Caltech) and as a postdoc with Prof. James Heath (Caltech). I have over ten years of experience in peptide synthesis, synthetic organic chemistry, biochemistry, and cell biology. The focus of my graduate work in the laboratory of Prof. Rich Roberts was the incorporation of unnatural amino acids to increase the proteolytic stability and drug-like properties of mRNA display libraries.
My innovations in this area make me especially suited to develop tetrazole-containing unnatural amino acids to increase the cell permeability and bio-stability of caspase imaging probes. During my postdoctoral work at the NanoSystems Biology Cancer Center (Caltech), I employed in situ click chemistry to design novel branched peptide architectures which were used to image Akt activation in ovarian cancer cells. This work has provided me with extensive experience in azide-based click chemistry making me well-suited to rapidly carry out the tetrazole syntheses described in the proposal. My appointment as an Assistant Professor in the Department of Cancer Systems Imaging at The University of Texas M.D. Anderson Cancer Center will enable me to translate fluorescence-based caspase probes into optical and PET imaging agents for pre-clinical development.
Education & Training
|2007||California Institute of Technology, Pasadena, CA, USA, PHD, Biochemistry and Molecular Biophysics|
|2000||The Johns Hopkins University, Baltimore, MD, USA, BA, Biology|
|2007-2011||Postdoctoral Fellowship, California Institute of Technology, Pasadena, CA|
Experience & Service
Assistant Professor, Department of Cancer Systems Imaging, Division of Diagnostic Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX, 2013 - 2022
Assistant Professor, Rice University, Houston, TX, 2012 - 2016
Honors & Awards
|2016||Robert M. Chamberlain Distinguished Mentor Award-Winner 2016, UT MDACC|
|2015||Robert M. Chamberlain Distinguished Mentor Award Finalist-2015, UT MDACC|
|2013||Moonshot Knowledge Gap Award, UTMDACC|
|2009||Poster Award, NCI Principal Investigators Meeting, NCI Principal Investigators Meeting|
|2008||NIH/NCI NRSA Postdoctoral Fellowship # F32CA136150, NCI|
|2006||ASBMB Conference, Graduate Travel Fellowship, ASBMB|
|2003||NIH Bioorganic Training Grant|
|2001||Lucy Mason Clark Fellowship, The California Institute of Technology|
|2000||Phi Beta Kappa, The Johns Hopkins University|
|2000||Milton Blumenfeld Scholarship, The Johns Hopkins University|
|1998||Howard Hughes Summer Research Fellowship, HHMI|
|1996||National Merit Scholar|
- Zacharias NM, Baran N, Shanmugavelandy SS, Lee J, Velez Lujan J, Dutta P, Millward SW, Cai T, Wood CG, Piwnica-Worms D, Konopleva M, Bhattacharya PK. Assessing Metabolic Intervention with a Glutaminase Inhibitor in Real-time by Hyperpolarized Magnetic Resonance in Acute Myeloid Leukemia. Mol Cancer Ther. e-Pub 2019. PMID: 31387889.
- Yang H, Shu Z, Jiang Y, Mao W, Pang L, Redwood A, Jeter-Jones SL, Jennings NB, Ornelas A, Zhou J, Rodriguez-Aguayo C, Bartholomeusz G, Iles LR, Zacharias NM, Millward SW, Lopez-Berestein G, Le XF, Ahmed AA, Piwnica-Worms H, Sood AK, Bast RC, Lu Z. 6-Phosphofructo-2-Kinase/Fructose-2,6-Biphosphatase-2 Regulates TP53-Dependent Paclitaxel Sensitivity in Ovarian and Breast Cancers. Clin Cancer Res. e-Pub 2019. PMID: 31391192.
- Sutton MN, Huang GY, Liang X, Sharma R, Reger AS, Mao W, Pang L, Rask PJ, Lee K, Gray JP, Hurwitz AM, Palzkill T, Millward SW, Kim C, Lu Z, Bast RC. DIRAS3-Derived Peptide Inhibits Autophagy in Ovarian Cancer Cells by Binding to Beclin1. Cancers (Basel) 11(4), 2019. e-Pub 2019. PMID: 31003488.
- Zacharias NM, Ornelas A, Lee J, Hu J, Davis JS, Uddin N, Pudakalakatti S, Menter DG, Karam JA, Wood CG, Hawk ET, Kopetz S, Vilar E, Bhattacharya PK, Millward SW. Real-Time Interrogation of Aspirin Reactivity, Biochemistry, and Biodistribution by Hyperpolarized Magnetic Resonance Spectroscopy. Angew Chem Int Ed Engl 58(13):4179-4183, 2019. e-Pub 2019. PMID: 30680862.
- Zacharias N, Lee J, Ramachandran S, Shanmugavelandy S, McHenry J, Dutta P, Millward S, Gammon S, Efstathiou E, Troncoso P, Frigo DE, Piwnica-Worms D, Logothetis CJ, Maity SN, Titus MA, Bhattacharya P. Androgen Receptor Signaling in Castration-Resistant Prostate Cancer Alters Hyperpolarized Pyruvate to Lactate Conversion and Lactate Levels In Vivo. Mol Imaging Biol 21(1):86-94, 2019. PMID: 29748904.
- Engel BJ, Gammon ST, Chaudhari R, Lu Z, Pisaneschi F, Yang H, Ornelas A, Yan V, Kelderhouse L, Najjar AM, Tong WP, Zhang S, Piwnica-Worms D, Bast RC, Millward SW. Caspase-3 Substrates for Non-Invasive Pharmacodynamic Imaging of Apoptosis by PET/CT. Bioconjug Chem 29(9):3180-3195, 2018. e-Pub 2018. PMID: 30168713.
- Kanikarla-Marie, P., Kopetz, S., Hawk, E.T., Millward, S.W., Sood, A.K., Gresele, P., Overman, M, M., Honn, K., Menter, D.G.. Bioactive Lipid Metabolism in Platelet "First Responder" and Cancer Biology. Cancer and Metastasis Reviews 37(2-3):439-454, 2018.
- Ornelas A, Zacharias-Millward N, Menter DG, Davis JS, Lichtenberger L, Hawke D, Hawk E, Vilar E, Bhattacharya P, Millward SW. Beyond COX-1: the effects of aspirin on platelet biology and potential mechanisms of chemoprevention. Cancer Metastasis Rev 36(2):289-303, 2017. PMID: 28762014.
- Pisaneschi F, Kelderhouse LE, Hardy A, Engel B, Mukhopadhyay U, Gonzalez-Lepera C, Gray JP, Ornelas A, Takahashi TT, Roberts RW, Fiacco SV, Piwnica-Worms D, Millward SW. An automated, resin-based method to enhance the specific activity of fluorine-18 clicked PET radiotracers. Bioconjug Chem 28(2):583-589, 2017. PMID: 28150941.
- Ornelas A, McCullough CR, Lu Z, Zacharias NM, Kelderhouse LE, Gray J, Yang H, Engel BJ, Wang Y, Mao W, Sutton MN, Bhattacharya PK, Bast RC Jr, Millward SW. Induction of autophagy by ARHI (DIRAS3) alters fundamental metabolic pathways in ovarian cancer models. BMC Cancer 16(1):824, 2016. PMID: 27784287.
- Fiacco SV, Kelderhouse LE, Hardy A, Peleg Y, Hu B, Ornelas A, Yang P, Gammon ST, Howell SM, Wang P, Takahashi TT, Millward SW, Roberts RW. Directed Evolution of Scanning Unnatural-Protease-Resistant (SUPR) Peptides for in Vivo Applications. ChemBioChem 17(17):1643-51, 2016. e-Pub 2016. PMID: 27465925.
- Washington MN, Suh G, Orozco AF, Sutton MN, Yang H, Wang Y, Mao W, Millward S, Ornelas A, Atkinson N, Liao W, Bast RC, Lu Z. ARHI (DIRAS3)-mediated autophagy-associated cell death enhances chemosensitivity to cisplatin in ovarian cancer cell lines and xenografts. Cell Death Dis 6(8):e1836, 2015. e-Pub 2015. PMID: 26247722.
- Deyle KM, Farrow B, Qiao Hee Y, Work J, Wong M, Lai B, Umeda A, Millward SW, Nag A, Das S, Heath JR. A protein-targeting strategy used to develop a selective inhibitor of the E17K point mutation in the PH domain of Akt1. Nat Chem 7(5):455-62, 2015. e-Pub 2015. PMID: 25901825.
- Howell SM, Fiacco SV, Takahashi TT, Jalali-Yazdi F, Millward SW, Hu B, Wang P, Roberts RW. Serum Stable Natural Peptides Designed by mRNA Display. Sci Rep 4:6008, 2014. e-Pub 2014. PMID: 25234472.
- Nag A, Das S, Yu MB, Deyle KM, Millward SW, Heath JR. A chemical epitope-targeting strategy for protein capture agents: the serine 474 epitope of the kinase Akt2. Angew Chem Int Ed Engl 52(52):13975-9, 2013. e-Pub 2013. PMID: 24254999.
- Millward SW, Agnew HD, Lai B, Lee SS, Lim J, Nag A, Pitram S, Rohde R, Heath JR. Click chemistry: from small molecule discovery to synthetic antibodies. Integr Biol (Camb) 5(1):87-95, 2013. e-Pub 2012. PMID: 22836343.
- Walker CM, Lee J, Ramirez MS, Schellingerhout D, Millward S, Bankson JA. A catalyzing phantom for reproducible dynamic conversion of hyperpolarized [1-13C]-pyruvate. PLoS One 8(8):e71274, 2013. e-Pub 2013. PMID: 23977006.
- Millward SW, Henning RK, Kwong GA, Pitram S, Agnew HD, Deyle KM, Nag A, Hein J, Lee SS, Lim J, Pfeilsticker JA, Sharpless KB, Heath JR. Iterative in situ click chemistry assembles a branched capture agent and allosteric inhibitor for Akt1. J Am Chem Soc 133(45):18280-8, 2011. e-Pub 2011. PMID: 21962254.
- Agnew HD, Rohde RD, Millward SW, Nag A, Yeo WS, Hein JE, Pitram SM, Tariq AA, Burns VM, Krom RJ, Fokin VV, Sharpless KB, Heath JR. Iterative in situ click chemistry creates antibody-like protein-capture agents. Angew Chem Int Ed Engl 48(27):4944-8, 2009. PMID: 19301344.
- Millward SW, Fiacco S, Austin RJ, Roberts RW. Design of cyclic peptides that bind protein surfaces with antibody-like affinity. ACS Chem Biol 2(9):625-34, 2007. PMID: 17894440.
- Millward SW, Takahashi TT, Roberts RW. A general route for post-translational cyclization of mRNA display libraries. J Am Chem Soc 127(41):14142-3, 2005. PMID: 16218582.
- Frankel A, Millward SW, Roberts RW. Encodamers: unnatural peptide oligomers encoded in RNA. Chem Biol 10(11):1043-50, 2003. PMID: 14652071.
- Li S, Millward SW, Roberts R. In vitro selection of mRNA display libraries containing an unnatural amino acid. Journal of American Chemical Society 124(34):9972-3, 2002. PMID: 12188645.
- Millward SW, Agnew HD, Pitram S, Lai BT, Hardman N.. Protein-Catalyzed Ligands for Molecular Imaging. International Hospital Equipment and Solutions:14-16, 2013.
Grant & Contract Support
|Title:||MD Anderson Institutional Support - Start-Up|
|Funding Source:||The University of Texas MD Anderson Cancer Center|
|Title:||SUPR Peptides for Targeted Radionuclide Delivery|
|Title:||SUPR Peptides for Immune Checkpoint Blockade Imaging|
|Funding Source:||CABI/GE In-Kind Research Award|
|Title:||Passenger Deletion of ENO1 as a Targetable Vulnerability in Cancer|
|Funding Source:||American Cancer Society (ACS)|
|Title:||Nernstian Probes as Vectors for Imaging and Therapeutic Modalities in Glioblastoma|
|Title:||Targeted Inhibition of Autophagy for Treatment of Dormant Ovarian Cancer|
|Funding Source:||Cancer Prevention & Research Institute of Texas (CPRIT)|