Mitochondrial Metabolism, Oxidative Stress, ER Stress, and Receptor Targeted Theranostics and Alpha Particle Targeted Therapy for Neuroendocrine tumors in Children and Adults (and related tumor biology and radiation biology).

Michael K Schultz PhD is an Associate Professor of Radiology, Pediatrics, Chemistry and Radiation Oncology (Free Radical and Radiation Biology Program) at the University of Iowa. Dr. Schultz’s lab focuses on tumor cell biology, radiation biology, peptide based ligand development, and radiochemistry for the development of image-guided radionuclide based therapies for cancer. The lab focuses on NETs, related pediatric brain tumors, and metastatic melanoma. With underlying support from the NET SPORE (PI M. Sue O’Dorisio MD PhD). Dr. Schultz’s lab is laying a foundation for alpha particle targeted therapy for these cancers through three basic initiatives supported by the NET SPORE and other NIH/NCI funding. (1) Image-guided peptide theranostic development; (2) Enhanced dosimetry modeling focused on alpha particle interactions in the tumor microenvironment; and (3) Radiopharmaceutical production automation for theranostic agents. The lab is focused on the theranostic pair of radionuclides ²⁰³Pb for SPECT imaging and ²¹²Pb for alpha + beta particle therapy for cancer. (4) Oxidative metabolism and the role of mitochondrial ROS metabolism in the acquisition of resistance to cancer chemotherapies with a focus on the relationships between ROS metabolism, ER stress, autophagic flux, and acquisition of resistance. These projects are outlined briefly in the following synopses.

1. New Image-guided Alpha Particle Therapy for NETs in Children and Adults
Graduate Student: Captain Dongyoul Lee

Neuroendocrine tumors (NETs) are a rare form of cancer whose incidence is increasing. In the development of effective therapy, high expression of somatostatin receptor subtype 2 (SSTR2) has been identified as a potential target for drug delivery, including peptide receptor radionuclide therapy using DOTA⁰-Tyr³-octreotide (DOTATOC). While beta particle therapies using ⁹⁰Y/¹⁷⁷Lu have been extensively examined, the potential advantages of alpha particle therapy have been relatively unexplored. Within this context, we are developing a new image-guided ²⁰³Pb(imaging)/²¹²Pb(therapy) approach that we anticipate will impart a higher RBE (relative biological effectiveness) via targeted alpha particle deposition in NETs and improve outcomes compared to current beta particle therapies. Our initial studies employed pancreatic carcinoid (BON-1) cells implanted subcutaneously in nude mice and a bio-distribution study was conducted by injecting 1 µCi of ²⁰³Pb/²¹²Pb-DOTATOC via tail vein. Mice were euthanized at 1h, 3h, and 24h post-injection (n=3); tissues of interest were harvested and radioactivity measured. These data were used to inform a SPECT/CT imaging study (180 µCi of ²⁰³Pb-DOTATOC was injected via tail vein) at 1 h post injection. A pilot therapeutic study was then conducted in BON-1 tumor bearing mice (3 groups: control, single dose, and 3 fractionated doses; total dose ~120µCi of ²¹²Pb-DOTATOC). Ongoing survival studies reveal a significant survival benefit and tumor control in ²¹²Pb-DOTATOC treated NET tumor bearing mice relative to untreated mice.  Excellent tumor contrast was observed in the first ²⁰³Pb-DOTATOC SPECT/CT images of human NETs obtained in these pilot studies. Biodistribution and imaging studies informed  ²¹²Pb-DOTATOC therapy in which significant survival improvement and reduction in tumor growth was observed in human NET bearing mice. These studies demonstrated that the ²⁰³Pb/²¹²Pb theranostic combination is a promising alternative for image-guided radionuclide therapy for NETs and other SSTR2 expressing tumors.

2. Modeling cell and tumor micro-metastasis dosimetry with Particle and Heavy Ion Transport code System (PHITS) for receptor-targeted alpha radionuclide therapy.
Graduate Student: Captain Dongyoul Lee (Human Toxicology Program)

Tumor dosimetry for peptide receptor radionuclide therapy (PRRT) is critical to therapy planning and predicting therapeutic outcomes. While dosimetry for beta emitters has been studied extensively, the dosimetry of alpha particle emissions in the tumor microenvironment is relatively unexplored. In this study, we characterized the energy deposition of several alpha emitters (²¹²Pb, ²¹³Bi, and ²²⁵Ac), in terms of S-values, for cells and tumor metastases using Particle and Heavy Ion Transport code System (PHITS). Two widely used beta emitters (⁹⁰Y and ¹⁷⁷Lu) were also considered for comparison. PHITS was validated by comparing S-values of ⁹⁰Y (dominated by beta emission) and ²¹²Po (pure alpha emitter) with the MIRD cellular S-values. Two theoretical concentric spheres were constructed, representing the cell membrane and the nucleus, and the radionuclides were assumed to be evenly distributed within the cells. The PHITS simulation showed 3-12% lower S-values for ⁹⁰Y, but agreed within 4% with the MIRD cellular S-values for ²¹²Po. The contribution of internalization to the S-values was then investigated with the same geometry of the cell by modifying the source definition from all membrane bound (0% internalized) to fully internalized within the cell (100% internalized) in 20% increments. The S-values arising with 100% internalization were ~1.5 fold higher for the entire cell and 2-3 fold higher for the nucleus when compared to 0% internalization of the radioactive atom. This suggested that internalization via radio-labeled peptides will increase the relative biological effectiveness of the radiotherapeutics. For micro-metastases dosimetry, spheres with various radii were constructed and S-values were acquired. S-values from PHITS were within 6% and 4% differences for ⁹⁰Y and ¹⁷⁷Lu respectively when compared with the data of Hindie et al. (J Nucl Med, 2016. 57;5). Alpha emitters deposited significantly higher doses to the tumor metastases of various size relative to beta emitters, representing 60-140 times higher doses for ²¹²Pb and ²¹³Bi and 190-620 times higher doses for ²²⁵Ac than ¹⁷⁷Lu respectively. Results substantiate emerging evidence that alpha emitters may be more effective for PRRT due to preferred dose deposition profiles.

3. Automated cassette-based production of high specific activity [^203/212Pb]peptide-based theranostic radiopharmaceuticals for image-guided radionuclide therapy for cancer. 
Graduate Student: Mengshi Li (Human Toxicology Program)

Receptor-targeted image-guided radionuclide therapy is increasingly recognized as a promising approach to treating cancer. In particular, the potential for clinical translation of receptor-targeted alpha-particle (α-) therapy is receiving considerable attention; and several recent works have highlighted the potential advantages of α-therapy. Alpha emitters are emerging as an attractive alternative (to b-emitters) due to higher linear-energy transfer (LET) (100 keV/µm) and resultant-significant increase in the intensity of ionizations (primary and secondary) along the relatively short path length that α-particles travel in tissue (compared to b-particles). These properties have been shown to result in an increased incidence of double-strand DNA breaks and improved-localized cancer-cell damage that convey the potential for more effective tumor-cell-specific killing with less damage to adjacent-normal cells (i.e., improved relative biological effectiveness; RBE). For example, recent studies in patients with advanced-stage castration-resistant metastatic prostate cancer provide compelling evidence that α-therapy (using [²²⁵Ac]PSMA617) has the potential to deliver a significantly more potent anti-cancer effect compared with b-therapy (using [¹⁷⁷Lu]PSMA617). (Kratochwil et al. 2016, Kratochwil et al. 2016) Numerous other studies demonstrate the potential of α-emitters for cancer therapy using radionuclides ²²⁵Ac, ²¹²Bi, ²¹³Bi, and ²¹¹At. Generator-produced ²¹²Pb (which decays to alpha emitters ²¹²Bi and ²¹²Po) is a particularly promising radionuclide for receptor-targeted α-particle therapy for metastatic melanoma and neuroendocrine tumors, and other cancers.

In our proposed application, the gamma(g)-emitting radionuclide ²⁰³Pb is being explored as the imaging surrogate for the therapeutic nuclide ²¹²Pb. The use of an isotope of the same element adds confidence to predictions that images collected are an appropriate representation of the expected pharmacokinetics/biodistribution of the therapeutic ligand. Within this context, our laboratories are pursuing ²⁰³Pb (half life t_1/2 = 52 h; gamma-ray intensity 81%; 279 keV) and ²¹²Pb (t_1/2 = 11 h; 100% b decay to α-emitters ²¹²Bi and ²¹²Po) as elementally-matched radionuclides. Importantly, the decay of ²¹²Pb includes the emission of a gamma ray with an energy (238keV) that has the potential to enable direct imaging via SPECT of [²¹²Pb]-labeled peptides. While this property of ²¹²Pb nuclear decay may present opportunities for direct imaging of the biodistribution of [²¹²Pb]-labeled peptides in the future, the use of ²⁰³Pb enables a non-invasive ²⁰³Pb SPECT (or SPECT/CT) image to be collected in advance of ²¹²Pb receptor-directed radiotherapy, with minimal risk of an adverse event. Thus, the potential value of this approach also conveys an improved patient selection for inclusion in clinical trials and a higher likelihood for approvals of ²¹²Pb labeled therapies. In addition, ²⁰³Pb is conveniently produced by commercial cyclotron, and ²¹²Pb is obtained (for radiopharmaceutical purposes) via a ²²⁴Ra/²¹²Pb generator. Advanced studies to develop a more detailed understanding of the potential for migration of ²¹²Pb decay-product progeny (i.e., ²¹²Bi; ²¹²Po) away from the decay of ²¹²Pb in vivo are an important aspect of current research in our laboratories and beyond the scope of the current article.

The Schultz laboratory has developed an automated cassette-based approach to ^203/212Pbradiolabeling and purification of chelator-modified peptides that can be easily integrated into routine clinical production. Extraction chromatography was used to facilitate pre-concentration of both cyclotron-produced ²⁰³Pb and generator produced ²¹²Pb. An HPLC approach for isolation of final-product radiopharmaceutical was optimized to enable automation of ²⁰³Pb and ²¹²Pb radiolabeled peptides from unlabeled precursors and achievement of near theoretical specific activity (MBq nmol^-1). An examination of the analogous in vitro and in vivo biochemical behavior of the ²⁰³Pb and ²¹²Pb labeled peptides (in melanoma-tumor bearing mice) is presented as evidence that the bioactivity of the compounds (following automated production) is preserved. These studies further corroborate previous preclinical reports supporting the use of ²⁰³Pb as a surrogate-imaging radionuclide for use in advance of ²¹²Pb therapy. Results demonstrate the feasibility of automated preparation of ²⁰³Pb and ²¹²Pb radiopharmaceuticals for clinical use and provide guidance for further refinements potentially necessary to adapt the approach for other radiopharmaceutical platforms (e.g., antibodies; aptamers; and small molecules). The sum of the findings and observations presented here support the idea that ²⁰³Pb and ²¹²Pb represent a promising elementally-matched radionuclide pair that can be applied clinically for image-guided radionuclide therapy for melanoma; neuroendocrine tumors; and other cancers as well

4. Thiol-Redox Imbalance Mediates MAPK_i-Resistance via ER-Stress and Autophagy in Melanoma. Graduate Student: Somya Kapoor (Free Radical and Radiation Biology Program)

The incidence of melanoma is growing faster than any other cancer in the United States. Surgery (and surgery with external beam radiation) can be curative at early stages, but metastatic melanoma is lethal. Recent-breakthrough MAPK pathway inhibitors (MAPK_i) (e.g., BRAF_i + MEK_i) and immunotherapies (e.g., PD-1 inhibitors PD1_i) have significantly improved outcomes. However, despite the current revolution in melanoma treatment, low response rates (<50%), drug resistance (5-yr survival 17%), and adverse events remain as significant challenges to long-term quality of life for metastatic melanoma patients. Within this context, studies have established the role of autophagy in acquisition of drug-resistance in metastatic melanoma. Unfortunately, inhibiting autophagy alone did not have a significant effect in clinical trials. Emerging evidence further establishes a role of ER stress in mediating the acquisition of the autophagy resistance response to BRAF_i/MEK_i in melanoma. However, the therapeutic potential of simultaneously inhibiting autophagy and relieving ER stress for drug-resistant metastatic melanoma has not been explored.

Our data show that in vitro (A375, 451LU BRAF_i-sensitive melanoma cell lines), MAPK pathway inhibition (MAPK_i) via continuous administration of vemurafenib (BRAF_i) and cobimetinib (MEK_i) perturbs mitochondrial functioning, disturbing the oxidative state of the cell and consequently the ratio of oxidized to reduced glutathione (GSH). The disturbs the GSH ratio and disrupts the protein folding machinery in the endoplasmic reticulum (ER), which activates the unfolded protein response (UPR) to the accumulation of misfolded proteins (ER-stress) in the ER lumen. Our data further demonstrates that prolonged activation of the UPR initiates an adaptive response to MAPK_ivia activation of an autophagic response that conveys a resistant phenotype. Excitingly, our data further demonstrates that simultaneously relieving ER-stress (using FDA approved, 4-phenyl butyric acid; 4-PBA) and inhibiting autophagy (using FDA approved drug Plaquenil, hydroxychloroquine HCQ) inhibits adaptation to MAPK_i in melanoma cell lines (A375, 451LU). Our studies further demonstrate that administration of the combination of 4-PBA and HCQ in with BRAF inhibitor (vemurafenib) improved tumor response and overall survival of mice bearing metastatic melanoma xenograft tumors (BRAF_i-resistant metastatic melanoma cell lines 451-LUBR and A2058). The combination therapy (4PBA+HCQ+Vem) led to complete remission in 20% and partial remission in 30% of mice as compared to controls (mice treated with vemurafenib alone or in combination with 4-PBA and HCQ individually). Pathology analysis of tumors at the conclusion of the study further showed that in some cases tumors treated with our combination therapy differentiated into apparent non-malignant nevi.

Hypothesis: These results lead to the hypothesis that melanoma resistance to BRAFi is caused by metabolic rewiring that depletes cellular glutathione, leading to oxidative stress, ER-stress-and autophagy that together desensitizes melanoma to MAPK pathway inhibitors. My work involves the development of detailed understanding of the underlying mechanisms that drives the acquisition of resistance.

PUBLICATIONS

Selected Schultz Laboratory Peer-reviewed Publications (last 5 years)

Neuroendocrine Tumors, Peptide Ligand Development, and related Pediatric Brain Cancers.

1. Menda Y, O'Dorisio TM, Howe JR, Schultz MK, Dillon JS, Dick D, Watkins GL, Ginader T, Bushnell DL, Sunderland JJ, Zamba GKD, Graham M, O'Dorisio MS. (2017) Localization of Unknown Primary Site with [⁶⁸Ga]DOTATOC PET/CT in Patients with Metastatic Neuroendocrine Tumor. Journal of Nuclear Medicine. 2017 Jul;58(7):1054-1057. PMCID: PMC5493006.

2. Li M, Zhang X, Quinn TP, Lee D, Liu D, Kunkel F, Zimmerman BE, McAlister D, Olewine K, Menda Y, Mirzadeh S, Copping R, Sagastume, Johnson FL, & Schultz MK. Production of high specific activity [^203/212Pb]DOTA-conjugated radiopharmaceuticals for clinical image-guided radionuclide cancer therapy using an automated cassette-based system. Applied Radiation and Isotopes. 201;May 10;127:52-60. PMID: 28521118.

3. Schoenfeld, JD, Sibenaller, ZA, Cramer-Morales, KL, Mapuskar, KA, Wagner, BA, Sandhu, S, Carlisle, TL, Smith, MC, Abu Hejleh, T, Furqan, M, Berg, DJ, Zhang, J, Keech, J, Parekh, KR, Bhatia, S, Bodekar, KL, Ahmann, L, Vollstedt, S, Brown, H, Shanahan-Kauffman, EP, Schall, ME, Hohl, RJ, Clamon, GH, Smith, B, Greenlee, JD, Howard, MA, Monda, V, Riley, DP, Schultz, MK, Domann, FE, Cullen, JJ, Buettner, GR, Buatti, JM, Spitz, DR, Allen, BG. (2017). O₂^·- and H₂O₂-Mediated Disruption of Fe Metabolism Causes the Differential Susceptibility of Lung and Brain Cancer Cells to Pharmacological Ascorbate. Cancer Cell. 31(4); 487–500.

4. MuellerD, BreemanWAP, KletteI, Gottschald A, OdparlikA, BaehreM, TworowskaI, & Schultz MK (2016). Radiolabeling of DOTA-like conjugated peptides with generator-produced ⁶⁸Ga and using NaCl based cationic elution method. Nature Protocols. 11, 1057–1066 (2016).

5. Tworowska I, RanganathanD, ThamakeS, DelpassandE, Mojtahedi A, Schultz MK, Zhernosekov K, & Marx M. (2015). Radiosynthesis of clinical doses of ⁶⁸Ga-DOTATATE (GalioMedixTM) and validation of organic-matrix-based ⁶⁸Ge/⁶⁸Ga generators. Nuclear Medicine Biology, Volume 43, Issue 1, Pages 19–26.

6. Ghai A, Singh B; Hazari PP, Schultz MK, Parmar A, Kumar P, Sharma S, Dhawan D, Mishra AK. (2015). Radiolabeling optimization and characterization of ⁶⁸Ga labeled DOTA-polyamido-amine dendrimer conjugate - Animal biodistribution and PET imaging Results. Applied Radiation and Isotopes, 105; November, 40-46.

7. Kim Y, Seol DR, Mohapatra S, Sunderland JJ, Schultz MK, Domann FE, Lim T-H. (2014). Local Targeted Delivery of Micron-size RadioTherapy-Source using Temperature-Sensitive HydroGEL (RT-GEL). Radiotherapy and Oncology, Apr 1;88(5):1142-7.

8. Y Menda, LL Boles Ponto, Schultz MK, GKD Zamba, GL Watkins, DL Bushnell, MT Madsen, JJ Sunderland, MM Graham, TM O’Dorisio, MS O’Dorisio. (2013) Repeatability of Ga-68 DOTATOC PET Imaging in Neuroendocrine Tumors.  Pancreas, Apr 12.

9. Martin ME, Sue O'Dorisio M, Leverich WM, Kloepping KC, Walsh SA, & Schultz MK. (2013). Synthesis and preliminary in vitro and in vivo evaluation of “click” cyclized peptides in a melanoma model. Rec Res in Cancer Res. 194:149-75. PMCID: PMC3799893
10. Schultz MK, Mueller D, Watkins GL, Breeman WAP. (2012). A new automated NaCl based robust method for routine production of gallium-68 labeled peptides. Applied Radiation and Isotopes, Aug 31.

11. Mueller D, Klette I, Baum RP, Gottschaldt M, Schultz MK, Breeman WAP. (2012). Simplified NaCl Based ⁶⁸Ga Concentration and Labeling Procedure for Rapid Synthesis of ⁶⁸Ga Radiopharmaceuticals in High Radiochemical Purity. Bioconjugate Chemistry. Aug 15;23(8) 1712-1717.

12. Baumhover NJ, Martin ME, Paramaswarappa SG, Kloepping KC, O’Dorisio MS, Pigge FC, & Schultz MK. (2011). Improved synthesis and biological evaluation of chelator-modified α-MSH analogues prepared by copper-free click chemistry. Bioorganic and Medicinal Chemistry Letters, Oct 1;21(19):5757-61. PMCID: PMC3171621.

PRESENTATIONS, POSTERS, ABSTRACTS, INVITED TALKS

Schultz Laboratory Invited Presentations and Accepted Abstracts (since 2010)

Neuroendocrine Tumors, Peptide Ligand Development, Theranostics, Cancer Cell Biology, and related Pediatric Brain Cancers.

1. Lee D, Li M, & Schultz MK. Modeling cell and tumor micro-metastasis dosimetry with Particle and Heavy Ion Transport code System (PHITS) for receptor-targeted alpha radionuclide therapy. (2017) Radiation Research Society Annual Meeting, Cancun, Mexico. October 15-18, 2017.

2. Kapoor S, Li M, Johnson FL, & Schultz MK. (2017) Redox imbalance mediates MAPKi-Resistance via UPR-Induced autophagy in metastatic melanoma. World Melanoma Research Congress, Brisbane, Australia. Oral presentation, October 18-20, 2017.

3. Schultz MK. The role of the academic entrepreneur in advancing imaging science. Invited “Spotlight” Presentation. (2017) World Molecular Imaging Society Annual Meeting, Sept 15, 2017.

4. Schultz MK. The role of the academic entrepreneur in technology transfer and university startup companies: The E-Myth and True Grit (2017). Invited Presentation. Washington University in St. Louis, May 23, 2017.

5. Hernandez-Vargas S, Ghosh SC, Voss J, Lee D, Schultz MK, Azhdarinia A. (2017). Synthesis and characterization of a ⁶⁸Ga/NIR labeled peptide for somatostatin receptor targeting. Accepted for oral presentation at the Annual Meeting of the Society of Nuclear Medicine, Denver, CO, June 10-14, 2017.

6. Li M, Lee D, & Schultz MK. (2017). Preparation of high specific activity Pb-203 and Pb-212 labeled peptides using an automated system. International Society of Radiopharmaceutical Sciences Meeting. Dresden, Germany. May, 2017.

7. Okoye, N., Rold, T.L., Berendzen, A.F., Zhang, X., White, R. M., Schultz, MK, Li, M., Dresser, T.P., Jurisson, S.S., Quinn, T.P., and Hoffman, T.J. (2017). Targeting the BB2 receptor in prostate cancer using a Pb-203 labeled peptide. Society of Nuclear Medicine and Molecular Imaging Annual Meeting. Denver, CO (June, 2017).

8. Tworowska I, Wagh N, Thamake S, Schultz MK, Delpassand ES (2017). ⁶⁴Cu-labeled dimeric glucosamine conjugates and their evaluation in metastatic melanoma- cancer cells. Society of Nuclear Medicine and Molecular Imaging Annual Meeting. Denver, CO (June, 2017).

9. Okoye N, Schultz MK, Jurisson S, Hoffman T. (2017). Purification of cyclotron-produced ²⁰³PbCl₂ and synthesis of a ²⁰³Pb labeled peptide. Northeast/Midwest NOBCChE Regional Conference (http://www.nexm2017.chem.pitt.edu/).

10. Schultz MK. Image-guided Receptor-targeted Radionuclide Therapy for Metastatic Melanoma (2017). Invited presentation; University of Missouri, Columbia; April 26^th, 2017.

11. Li M, LeeD, KapoorS, Liu D, & Schultz MK. (2017) Enhanced efficacy of image-guided targeted α-particle therapy for human metastatic melanoma by co-treatment of MAPK and HDAC inhibitors. Society for Melanoma Research Congress, Boston MA, Nov. 6-9; Abstract.

12. KapoorS, Li M, LeeD, Liu D, Johnson FL, & Schultz MK. (2017) BRAF_i induced thiol imbalance leads to BRAF_i adaptation via autophagic flux. Society for Melanoma Research Congress, Boston MA, Nov. 6-9; Abstract.

13. Schultz MK. Image-guided Receptor-targeted Radionuclide Therapy for Metastatic Melanoma (2016).  World Molecular Imaging Society 2016 Translational Imaging Symposium, Boston, MA.

14. Lee D, LiM. Liu D, O’DorisioMS & Schultz MK. (2016) New Image-guided Alpha Particle Therapy for NETs in Children and Adults. NANETS Annual Meeting, Denver, CO. Poster Presentation.

15. Eitrheim, E. S., Knight, A. W., Nelson, A. W., & Schultz, M. K. (2014). Dual Labeled Probe for Nuclear and Fluorescence Imaging. Radiobioassay and Radiochemical Measurements Conference, Knoxville, TN, 30 October 2014.

16. Knight, A. W., Peterson, M. C., & Schultz, M. K. (2014). Additional Uses for Sr and Pb Resins. Eichrom User’s Group Meeting at the Radiobioassay and Radiochemical Measurements Conference, Knoxville, TN, 28 October 2014.

17. Nelson, A. W., & Schultz, M. K. (2014). Polonium Analysis in Complex Samples. Eichrom User’s Group Meeting at the Radiobioassay and Radiochemical Measurements Conference, Knoxville, TN, 28 October 2014.

18. Eitrheim, E. S., & Schultz, M. K. (2014). Ion Exchange Chromatography (IX) verses Extraction Chromatography (EXC).  Eichrom User’s Group Meeting at the Radiobioassay and Radiochemical Measurements Conference, Knoxville, TN, 28 October 2014.

19. Kapoor S, Martin ME, & Schultz MK. (2014) Synthesis and initial biological evaluation of GRP78 targeted peptides for molecular imaging of metastatic melanoma. (Oral presentation). J Nucl Med. 2014; 55 (Supplement 1):443.

20. Tworowska I, Kapoor S, Kloepping K, Delpassand E & Schultz MK. Molecular imaging of metastatic melanoma using Ga-68 GLUT1 targeted glucosamines. J Nucl Med. 2014; 55 (Supplement 1):1045.

21. Schultz MK. (2013). 2^nd World Congress on Ga-68 Molecular Imaging and Peptide Targeted Radionuclide Therapy. Molecular imaging of pediatric patients with Ga-68 labeled peptides. Invited Presentation. February 27 – March 2, 2013. Chandigarh, India.

22. Schultz MK. (2013). 2^nd World Congress on Ga-68 Molecular Imaging and Peptide Targeted Radionuclide Therapy. Congress Highlights Presentation as Congress Vice President. February 27 – March 2, 2013. Chandigarh, India.

23. Schultz MK. (2012). Gordon Research Conference – Metals in Medicine. Radiochemistry and PET Imaging Applications of Generator Based Gallium-68. Invited Presenter. Andover, NH. June 24-29, 2012.

24. Sunderland JJ, Dick D, Schultz MK, Watkins GL, Sensoy L. (2013). Quantitative assessment of Ge-68 breakthrough from a commercial titanium-dioxide based Ge-68/Ga-68 generator. Society of Nuclear Medicine and Molecular Imaging Annual Meeting, Vancouver, British Columbia, CA. June 6-8. Poster 1186.

25. Menda Y, O'Dorisio TM, Graham M, Schultz MK, Dick D, Ponto LL, Dillon J, Bushnell D, Sunderland JJ, O'Dorisio MS. The diagnostic utility of Gallium-68 DOTATOC PET-CT in patients with suspected neuroendocrine tumors (NET). Society of Nuclear Medicine and Molecular Imaging Annual Meeting, Vancouver, British Columbia, CA. June 6-8. Presentation 1892.

26. Kloepping KC, Coleman MC, Wagner BA, Jacobus JA, Mapuskar KA, Buettner GR, Spitz DR, & Schultz MK. (2012) Free Radicals in Biology and Medicine, Vol. 53:S(2); S46-S46.

27. Schultz MK. (2012). Chelator additions to peptides for molecular imaging by ring strain promoted copper free click chemistry. Invited Faculty Continuing Education Seminar. Society of Nuclear Medicine Annual Meeting, Miami, FL. June 9.

28. Schultz MK. (2012). Molecular Imaging Advances for Pediatrics – [⁶⁸Ga]DOTATOC and the horizon for PET imaging of pediatric cancers. Invited Faculty Presentation. Pediatric Council Meeting. Society of Nuclear Medicine Annual Meeting. Miami, FL. June 11.

29. Kim Y, Seol D, Mohapatra S, Schultz MK, Domann FE, Lim T. (2012) Targeted Delivery of Micro-size Radiation Therapy-source Using Temperature-sensitive Hydrogel (RT-GEL). Int. J. Rad. Onc. Biol. Phys., Volume: 84   Issue: 3   Supplement: S   Pages: S134-S135   Published: NOV 1 2012.

30. Martin ME, Boese EA, O'Dorisio MS, Schafer B, Carr J, Howe J, & Schultz, MK. (2012) Molecular Targeting of G Protein-Coupled Receptors MC1R and VPAC1 for Positron Emission Tomography Imaging of Pancreatic Neuroendocrine Tumors. Pancreas, Volume: 41   Issue: 2   Pages: 340-340   Published: MAR 2012.

31. Schultz MK, Menda Y, O'Dorisio T, Ponto LLB, Thedes-Reynolds K, Sunderland JJ, Bushnell DL, Watkins GL, O'Dorisio MS. (2012) Generator Produced Ga-68 for Clinical Preparations of [Ga-68]DOTATOC for Imaging Neuroendocrine Tumor Patients: Initial Studies at the University of Iowa. Pancreas, Volume: 41   Issue: 2   Pages: 348-348   Published: MAR 2012

32. Schultz MK. (2012). Radionuclides for Molecular Imaging and Therapy of Cancer. Invited Faculty Lecture, Oregon State University, Host Alena Paulenova, Professor of Radiochemistry. April 21, 2012.

33. Schultz MK. (2012). Multireceptor targeting of GPCRs for Molecular Imaging and Radionuclide Therapy of Cancer. Invited Faculty Lecture, University of Missouri Research Reactor, Columbia, MO. Host Cathy Cutler, Research Scientist.

34. Schultz MK. (2011). The Radiochemistry Program at the University of Iowa: molecular imaging and the need for continued support of the DOE isotopes program. 57th Annual Radiobioassay and Radiochemical Measurements Conference. Destin, FL. October 31 - November 4.

35. Trivedi, ER, Blumenfeld CM, Schultz MK, Meade TJ, Barrett AGM, Hoffman, BM. (2012). Multimodal tumor imaging and therapy with heteroatom functionalized porphyrazines. ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY  Volume: 241   Meeting Abstract: 627-ORGN   Published: MAR 27 2011

36. Schultz MK. The role of ⁶⁸Ga for molecular imaging of cancer in the United States. Invited Scientific Faculty. (2012). Invited Scientific Faculty. Society of Nuclear Medicine Mid Winter Meeting. Orlando, FL. January 23-26.

37. Schultz, MK, Martin ME, Schafer B, and O’Dorisio MS (2011). Synthesis and evaluation of Gallium-68 labeled peptides for molecular imaging of childhood medulloblastoma. Invited Scientific Faculty. First World Congress on Gallium-68 and PRRT, Bad Berka, DE, June 23-26.

38. Schultz, MK, Martin ME, Schafer B, and O’Dorisio MS (2011). Synthesis and evaluation of Gallium-68 labeled peptides for molecular imaging of childhood medulloblastoma. Invited Scientific Faculty. First World Congress on Gallium-68 and PRRT, Bad Berka, DE, June 23-26.

39. MartinME, SchaferB, ShuttDC, KloeppingKC, WalshS, Boles-PontoLL, WeilandNA, O’DorisioTM, O’DorisioMS, SchultzMK. (2010). Development of ⁶⁸Ga labeled neuropeptide Y analogs for imaging neuroblastoma. 42^nd SNM India Meeting, Invited Honorary Faculty, Chandigarh, India.

40. Molly E. Martin, Daniel Calva-Cerqueira, Blanca Schafer, Whitney Leverich, Michael K. Schultz, Damon C. Shutt, Thomas M. O’Dorisio, M. Sue O’Dorisio, and James Howe. (2009) Discovery of G protein coupled receptor tumor signatures and identification of Positron Emission Tomography imaging targets in ileal and pancreatic neuroendocrine tumors. NANETS Annual Meeting, Charlotte, NC. October 2-3, 2009.