Browsing by Author "Oldan, Jorge D"

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    Increased tryptophan, but not increased glucose metabolism, predict resistance of pembrolizumab in stage III/IV melanoma.
    (Oncoimmunology, 2023-01) Oldan, Jorge D; Giglio, Benjamin C; Smith, Eric; Zhao, Weiling; Bouchard, Deeanna M; Ivanovic, Marija; Lee, Yueh Z; Collichio, Frances A; Meyers, Michael O; Wallack, Diana E; Abernethy-Leinwand, Amber; Long, Patricia K; Trembath, Dimitri G; Googe, Paul B; Kowalski, Madeline H; Ivanova, Anastasia; Ezzell, Jennifer A; Nikolaishvili-Feinberg, Nana; Thomas, Nancy E; Wong, Terence Z; Ollila, David W; Li, Zibo; Moschos, Stergios J
    Clinical trials of combined IDO/PD1 blockade in metastatic melanoma (MM) failed to show additional clinical benefit compared to PD1-alone inhibition. We reasoned that a tryptophan-metabolizing pathway other than the kynurenine one is essential. We immunohistochemically stained tissues along the nevus-to-MM progression pathway for tryptophan-metabolizing enzymes (TMEs; TPH1, TPH2, TDO2, IDO1) and the tryptophan transporter, LAT1. We assessed tryptophan and glucose metabolism by performing baseline C11-labeled α-methyl tryptophan (C11-AMT) and fluorodeoxyglucose (FDG) PET imaging of tumor lesions in a prospective clinical trial of pembrolizumab in MM (clinicaltrials.gov, NCT03089606). We found higher protein expression of all TMEs and LAT1 in melanoma cells than tumor-infiltrating lymphocytes (TILs) within MM tumors (n = 68). Melanoma cell-specific TPH1 and LAT1 expressions were significantly anti-correlated with TIL presence in MM. High melanoma cell-specific LAT1 and low IDO1 expression were associated with worse overall survival (OS) in MM. Exploratory optimal cutpoint survival analysis of pretreatment 'high' vs. 'low' C11-AMT SUVmax of the hottest tumor lesion per patient revealed that the 'low' C11-AMT SUVmax was associated with longer progression-free survival in our clinical trial (n = 26). We saw no such trends with pretreatment FDG PET SUVmax. Treatment of melanoma cell lines with telotristat, a TPH1 inhibitor, increased IDO expression and kynurenine production in addition to suppression of serotonin production. High melanoma tryptophan metabolism is a poor predictor of pembrolizumab response and an adverse prognostic factor. Serotoninergic but not kynurenine pathway activation may be significant. Melanoma cells outcompete adjacent TILs, eventually depriving the latter of an essential amino acid.
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    Predictors of survival in 211 patients with stage IV pulmonary and gastroenteropancreatic mIBG positive neuroendocrine tumors treated with I-131 mIBG.
    (Journal of nuclear medicine : official publication, Society of Nuclear Medicine, 2018-05-18) Kane, Ari; Thorpe, Matthew P; Morse, Michael A; Howard, Brandon A; Oldan, Jorge D; Zhu, Jason; Wong, Terence Z; Petry, Neil A; Reiman, Robert; Borges-Neto, Salvador
    Purpose: This retrospective analysis identifies predictors of survival in a cohort of patients with mIBG positive stage IV pulmonary and gastroenteropancreatic neuroendocrine tumor (P/GEP-NET) treated with I-131 mIBG therapy, in order to inform treatment selection and post-treatment monitoring. Methods: Survival, symptoms, imaging, and biochemical response were extracted via chart review from n = 211 P/GEP-NET patients treated with mIBG between 1991-2014. For patients with computed tomography (CT) follow up (n = 125), imaging response was assessed by Response Evaluation Criteria on Solid Tumors (RECIST) 1.1 where images were available (n = 76) or by chart review of the radiology report where images could not be reviewed (n = 49). Kaplan Meier analysis and Cox multivariate regression estimated survival and progression free survival benefits predicted by initial imaging, biochemical and symptomatic response. Results: All patients had stage IV disease at time of treatment. Median survival was 29 months from time of treatment. 71% of patients demonstrated symptomatic response with median duration of symptomatic relief of 12 months. Symptomatic response at first follow-up predicted a survival benefit of 30 months (p<0.001). Biochemical response at first clinical follow up was seen in 34% of patients with stability of labs in 48%; response/stability vs. progression extended survival 40 months (p<0.03). Imaging response (20% of patients) or stability (60%) at initial 3 month follow up imaging extended survival 32 months (p<0.001). Additionally, multiple mIBG treatments was associated with 24 months additional survival (p<0.05). Conclusion: Therapeutic I-131-mIBG for metastatic pulmonary or gastroenteropancreatic neuroendocrine tumors appears to be an effective means of symptom palliation. Imaging, biochemical, and symptomatic follow-up each help prognosticate expected survival following mIBG therapy. Multiple rounds of mIBG are associated with prolonged survival; it is unclear whether this represents cause or effect.