7/31/18. Expanding Options for the Treatment of Canine Cushing s Disease. Introduction. Cushing s in Man

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1 Expanding Options for the Treatment of Canine Cushing s Disease David Bruyette, DVM, DACVIM Chief Medical Officer Anivive Lifescience 3750 Schaufele Rd, Suite 100 Long Beach, CA david@anivive.com People: Third most common intracranial tumor (10-15%) Incidentaloma s in 1 in 6 adults (16 %) Clinically apparent tumor in 1 in 1000 adults Tumors causing Cushing s disease per 1 million adults Dogs: Introduction Tumors causing Cushing s disease 1.0 per 1,612 dogs 90, ,000 new cases/year Cushing s in Man ACTH Dependent 80% Pituitary adenoma 70% Ectopic ACTH 10% Ectopic CRH ACTH Independent 20% Adrenal adenoma 10% Adrenal carcinoma 5% Macronodular hyperplasia 1-2 % McCune Albright 1-2 % Primary pigmented nodular 1-2% 1

2 Cushing s in Dogs ACTH Dependent 85% Pars distalis 60% Pars intermedia 25% ACTH Independent 10% Adrenal adenoma 5% Adrenal carcinoma 5% Meal/Food Induced Ectopic Pathophysiology Lack of diurnal variation of ACTH and cortisol in dogs and cats. Episodic secretion of ACTH. Estimated 90, ,000 new canine cases diagnosed per year. Pathophysiology Chronic hypercortisolemia results in clinical signs of Cushing s Disease 2

3 Pathophysiology Pituitary carcinoma Pituitary hyperplasia Adenoma of pars distalis ~70% of dogs with PDH Adenoma of pars intermedia ~ 20-30% of dogs with PDH Normal Pituitary Size P/B ratio <.31 Pituitary height mm Pituitary Size Enlarged in % P/B ratio Tumors > 1 cm in 31 % Neurologic signs with masses greater than 8.5 mm 3

4 Clinical Signs - Man Obesity 39-96% Facial plethora 82-90% Decreased libido 24-90% Muscle weakness 60-82% Menstrual irregularity 74-80% Glucose intolerance 50-80% Hypertension 62-78% Hirsutism 72-75% Psychiatric disorders 53-70% Clinical Signs - Dog Polyuria 80% Polydipsia 80% Alopecia 80% Polyphagia 70% Hypertension 70% Abdominal distention 60% Panting 35 % Obesity 25% Behavior change 25% Diagnosis- Man Urinary free cortisol (UFC) Late night salivary cortisol outpatients Midnight serum cortisol inpatients Dexamethasone suppression testing 24 hour urine cortisol 8 am serum cortisol Minimum of 2 positive test results 4

5 Diagnosis - Dog ACTH Stimulation Test Low Dose Dexamethasone Suppression Test (LDDS) Urine Cortisol:Creatinine Ratio (UCCR) Salivary Free Cortisol Testing Hair Cortisol Concentrations Discriminatory Tests - Man Plasma ACTH Normal or high ACTH dependent Pituitary MRI Low ACTH independent Adrenal imaging ACTH Dependent No pituitary mass Bilateral IPSS to identify gradient. If no gradient: Ectopic: CRH stim/hddst, advanced imaging +/-scintigraphy Discriminatory Tests - Dog Most commonly used tests: ACTH concentrations HDDST Ultrasonic examination of adrenal glands 2-3 % incidence of incidentaloma MRI 5

6 Deciding on Treatment Options Corticotroph Somatotroph Oral ectoderm Rpx/HesX-1 Pax-6 Six-1,3 Isl-1 Ptx1,2 Lhx-3 Lhx-4 Prop-1 GATA-2 Tpit NeuroD1/β2 Rathke s pouch stem cell Pit-1 Lhx-4 GATA-2 SF-1 ERα Somatotroph stem cell ERα TEF GATA-2 GH repressor Pit-1β ERα Mammosomatotroph Pit-1β Lactotroph GH repressor Gonadotroph Thyrotroph Transcription factor Phenotype 6

7 Pituitary Corticotroph Ontogeny Anterior lobe corticotrophs first to differentiate in all species Migration into PI in dogs and horse and zona intermedia in man Canine pars intermedia 2 distinct corticotroph subtypes Bioactive and iacth 50% of that in pars distalis Biosynthesis and Secretion of ACTH Anterior Pituitary Controlled by different transcription factors (CRH, VP and LIF) at the level of the POMC gene CRH induces expression of: c-foc, NGF1-B, Nur77 Biosynthesis and Secretion of ACTH BMP-4 Inhibits POMC gene expression through SMAD s (SMAD1) leading to decreased activity of Tpit and Pitx1; paracrine and autocrine effects Glucocorticoids Antagonize Nur77 7

8 Biosynthesis and Secretion of ACTH Pars Intermedia Innervated by dopaminergic neurons which inhibit synthesis of POMC Bromocriptine, selegilene, cabergoline, pergolide Hypothalamic vs Pituitary Hypothalamic origins Greater secretion of CRH and VP Defects in GR receptor Dec inhibitory effect of cortisol Inc POMC and CRH synthesis Aging and neurodegeneration Pars intermedia and hippocampus Decreased dopaminergic innervation Decreased D2 receptors Hyperplasia > Adenoma Hypothalamus vs Pituitary Hypothalamic origins Evidence for: Chronic stress and ageing > activation of HPA axis > corticotroph hyperplasia Mutations in GR gene > resistance to GC and development of an adenoma 8

9 Development of the Adenoma Pituitary Origin Oncogenes c-erb B2/neu c-myc and PKC RET and c-fos c-myc and RAS No documented link to ACTH producing tumors Development of the Adenoma Proto-oncogenes Tyrosine kinase c-myc over-expression PTTG? Expressed in proliferating cells 50 % in 1 corticotrophinoma Development of the Adenoma Tumor Suppressor Genes p53 possible role in invasive tumors Cell cycle inhibitory proteins p21, p27, p16, Rb1 Knock-out mice for Rb1 and p27 developed PI tumors 9

10 Development of the Adenoma Tumor Suppressor Genes Cell cycle inhibitory protein p27 in dogs: No difference between enlarged and non-enlarged pituitaries Trend towards increased expression in adenoma vs normal Development of the Adenoma Receptor Alterations CRHR and VPR3 over-expressed Stress down regulates CRHR but up regulates VPR3 expression Development of the Adenoma Receptor Alterations: LIFR in Dogs Co-expressed and localized with ACTH in controls cilifr preserved in adenoma and non-tumorous PI No mutations in LIFR gene nilifr may = adenoma 10

11 Development of the Adenoma Receptor Alterations GR s in dogs with adenoma s Inc expression of 11 HSD-2 Dec expression of 11 HSD-1 Dec cortisol in the region of the GR Influences growth of adenoma Trilostane and adenoma formation Development of the Adenoma Receptor Alterations Over-expression of Nur77 GC resistance Cellular proliferation Development of the Adenoma Regulation of Pituitary Growth Tpit required for POMC gene expression Humans Overexpressed in tumor vs normal Dogs No difference in expression No mutations in the cdna 11

12 Development of the Adenoma Receptor Alterations Humans Overexpression of D2 and SST5 Dogs Overexpression of D2 and SST2 Implications for pathogenesis and treatment options Development of the Adenoma Regulation of Pituitary Growth RXR and RAR Retinoic acid interacts with BMP SMAD and MAPK? Affects corticotroph growth POMS gene expression Defects in RXR/RAR Loss of regulation Corticotroph formation Development of the Adenoma Regulation of Pituitary Growth PPAR gamma Normal and abnormal corticotrophs Only ACTH producing cells Regulates POMC synthesis AtT20 in vitro vs in vivo Trials in humans with CD PPAR in dogs? 12

13 Medical Management Human FDA Approved Canine FDA Approved Pasireotide (Signifor) Somatostatin analog Mifepristone (Korlym) Glucocorticoid receptor antagonist Trilostane (Vetoryl) Adrenal enzyme inhibitor Selegiline (Anipryl) MAO-B inhibitor 13

14 Medical Management Pituitary Directed Therapy Human Somatostatin Receptor Octreotide Pasireotide Canine Somatostatin Receptor Octreotide Pasireotide SST 2 vs SST 5 Retinoic Acid Receptor Bexarotene PPAR Rosiglitazone Retinoic Acid Receptor 9-cis retinoic acid Medical Management Pituitary Directed Therapy Human Canine Dopaminergic Bromocriptine Cabergoline Dopaminergic Selegilene (MAO-B) Cabergoline Bromocriptine Serotonergic Cyproheptadine Serotonergic Cyproheptadine Medical Management Adrenal Directed Therapy Human Canine Ketoconazole Metyrapone Etomidate Mitotane (op-ddd) LCI699 NormoCort Trilostane Mitotane (op-ddd) Ketoconazole Metyrapone 14

15 Medical Management Peripherally Directed Therapy Human Canine Mifepristone Mifepristone Information only as an abortifacient MAKING THE CHOICE Future Pituitary Directed Therapy Medical management in vast majority of cases o,p DDD - Lysodren l-deprenyl - Anipryl Trilostane Modrenal, Vetoryl 15

16 Goals of Any Therapy Address Primary Disorder Control of Clinical Signs Prevention of Treatment Related Side-Effects Cost Novel therapeutic agents Role of surgical therapy Role of radiation therapy 9-cis Retinoic Acid Regulation of POMC gene expression Reduction in binding of transcription factors AP-1 and Nur77 Inhibits corticotrophinoma development and proliferation Binds to both retinoic acid and retinoid X receptors 16

17 Canine 9-cis Retinoic Acid Study Group 1: 2 mg/kg once a day for 180 days Group 2: Ketoconazole 20 mg/kg per day x 180 days Monitoring: Clinical signs, UCCR, endogenous ACTH, MSH, pituitary size Canine 9-cis Retinoic Acid Study Significant decreases in UCCR, ACTH, MSH and pituitary size during therapy. No decrease in MSH or ACTH in ketoconazole group, no change in pituitary size though there was a reduction in the UCCR Canine 9-cis Retinoic Acid Study Canine Study (PDH) Retinoic acid group: 17/22 dogs free of clincial signs of HAC 6-12 months after stopping therapy. 17

18 Pars Intermedia Tumors High alpha MSH Lack of suppression on LDDS/ HDDS Shorter remission times post surgery 25% of pituitary cases Dopaminergic therapy Canine Cabergoline Study 63 patients enrolled 40 treated with cabergoline 0.02 mg/kg PO q48 hours 23 treated with ketoconazole 10 mg/kg PO BID Canine Cabergoline Study Cabergoline group 24/40 responded after the first month 7/24 failed within 2-4 months Overall response rate 17/40 (43%) 16/40 no response after 2 months 18

19 Canine Cabergoline Study Cabergoline group Responding dogs had significantly smaller tumors or normal sized pituitaries All dogs with PI tumors (7/40) had complete biochemical, anatomic and clinical remission during the 4 year follow-up. Lack of available canine MSH assay in US Canine Pasireotide Study Group 1 (10 dogs): 0.03 mg/kg SC BID x 6 months Group 2 (10 dogs): 0.03 mg/kg SC BID with 3 2 month cycles (on/ off) 19

20 Pasireotide in Canine Macroadenoma No differences from baseline were identified in clinicopathologic values, ACTH stimulation test results, or plasma ACTH concentration at the 3- or 6-month assessment points. After 6 months of pasireotide treatment, 6 dogs had decreases in MRI-measured values, and 3 had increases. CONCLUSIONS AND CLINICAL RELEVANCE: Pasireotide as administered in this study had no noted adverse effects on dogs with PDH and macroadenoma successfully managed with standard treatment. Placebo-controlled, randomized studies are needed to determine whether pasireotide protects from the development of neurologic signs or improves outcome in dogs with pituitary macroadenomas. Lottati M, Bruyette DS. Outcomes of the addition of pasireotide to traditional adrenal-directed treatment for dogs with pituitarydependent hyperadrenocorticism secondary to macroadenoma: 9 cases ( ). J Am Vet Med Assoc 2018 Jun 1;252(11):

21 * 7/31/18 A. B. Breast Ca Testis EV EGFR ICD Canine Cushing Human Cushing E. 200 EV ICD C. ACTH (Fold) D. mrna (Fold) ** mrna levels (% control) * ** EV EGFR ICD EV EGFR ICD 0 Fukuoka et al, JCI 121: (12), 2012 gefitinib gefitinib EGFR in Pituitary Tumors Nuclear expression in canine and human tumors. Blocking EGFR with TKI resulted in decreased ACTH secretion and POMC expression. In murine corticotroph EGFR transfectants ACTH secretion and POMC expression was enhanced which was blocked with TKI. Treatment also decreased tumor size, corticosterone levels, blood glucose and omental fat in athymic nude mice with explanted ACTH secreting tumors. Fukuoka et al, JCI 121: (12), 2012 Survival Data op-ddd 6 month mortality = 17% 52 % relapse Survival at 1, 2 and 3 years 80, 69, and 61 % (129 dogs) 80, 59, and 45 % (54 dogs) 72, 47, and 30 % (200 dogs) 11/200 (5%) macroadenoma DFI at 1, 2 and 3 years 77, 53 and 44% (129 dogs) 21

22 Survival Data Surgery (TSH) Remission 85 % 6 month mortality = 12 % 25 % relapse Survival at 1, 2 and 3 years 84, 76, and 72 % (150 dogs) DFI at 1, 2 and 3 years 88, 75 and 66 % (150 dogs) 22

23 Surgery (TSH; WLA; 26 dogs) 26 dogs with PDH 21/26 (81%) alive to discharge Median P/B ratio /26 (19%) died or euthanized Median P/B ratio /6 brain stem hemorrhage/infarct 1/6 cavernous sinus bleed 1/6 airway obstruction 1/6 pituitary carcinoma w/invasion PDH and Recurrence United States 21/21 (100%) initial remission 1/21 (5%) relapse Follow up days 23

24 Pituitary Size and PDH Median P/B ratio 0.33 ( ) Netherlands 78/181 (43%) normal pituitary size Median P/B ratio 0.38 ( ) Japan 6/25 (24%) normal pituitary size Median P/B ratio 0.74 ( ) WLA 0/26 (0%) normal pituitary size Hanson, Teske, Voorhout et al. J. Neurosurg Hara, Teshima, Taoda et al. J Vet Med Sci 2010 Mamelak, Owen, Bruyette. Vet Surg 2014 Netherlands 155/167 (92%) initial remission 36/155 (23%) relapse 118/181 (65%) sustained remission Japan 21/25 (84%) initial remission 3/21 (12%) relapse 18/25 (72%) sustained remission WLA 21/21 (100%) initial remission 1/21 (5%) relapse 20/21 (95%) sustained remission 24

25 Who is Whom s Best Friend? Pathogenesis Molecular events Receptor subtypes Treatment Options Medical Surgical Radiation Combination Acknowledgements: Harvey Cushing, MD Effects of hypophyseal transplantation following total hypophysectomy in the canine. Quart Jour Exper Physiol , 1909 Experimental Hypophysectomy. Bull Johns Hopkins Hosp ,