Innovations in Gynecologic Cancer Care 5/12/2017 Ovarian cancer integrative oncology: Principles, Practice and Outcomes Leanna J. Standish ND, PhD, MSAOM, FABNO Bastyr University Research Institute UW School of Medicine, Radiology May 12, 2017 Swedish Hospital lecture 1 Innovations in Gynecologic Cancer Care 5/12/2017 Integrative oncology is a new emerging medical discipline with: • Textbooks • Journals • International society • Board certification • Federal funding • NCI • NCCAM NCCIH 2 2 Innovations in Gynecologic Cancer Care 5/12/2017 Professional societies and board certification Board Certification in naturopathic oncology 2004 FABNO 3 3 Innovations in Gynecologic Cancer Care 5/12/2017 Basic philosophy of integrative oncology is that modalities such as acupuncture, nutrition, psychological counseling, some specific botanical and fungal ‘supplements’ can improve QOL. Basic philosophy of naturopathic oncology is that 1) the natural world and its medicine, both known and unknown, is able to provide safe and effective treatments for cancer patients to improve high quality survival; 2) cancer is also a mind‐body problem and requires psychological interventions. Goals of advanced IO in ovarian cancer includes improve chemo sensitivity, decrease dose‐limiting toxicities of chemotherapy, reduce risk of recurrence after primary cancer treatment, palliation of symptoms and improving quality of death & dying. 4 Innovations in Gynecologic Cancer Care 5/12/2017 Most of our best chemotherapy drugs originated from plants Plant Chemotherapy derivative Pacific Yew (Taxus brevifolia) paclitaxel, docetaxel, albumin‐bound paclitaxel Pink & Red Periwinkle (Catharanthus vincristine and vinblastine, vinorelbine roseus) Chinese “Happy Tree” (Camptotheca camptothecin acuminata) Mayapple (Podophyllum peltatum) teniposide and etoposide 5 5 Innovations in Gynecologic Cancer Care 5/12/2017 Curcumin NFKappaB inhibitor Increase P53 expression Green tea MTOR (serine/threonine kinase) inhibitor; P21 upreg Apoptosis by free radical MOA Bromelain cysteine proteinases with antimetastatic, antithrombotic antiedematous, fibrolytic, Quercetin histone deacetylase inhibitor Tyrosine kinase inhibitor Artemisinin Iron oxidative stress Ascorbate Oxidative burst in malignant cells Melatonin Proteosome inhibitor Anti-estrogen Trametes versicolor (Lu and Disis UW TVG Immune modulator via 2011-2012) Toll-like 2 receptor agonist Dectin-1 agonist Inflammasome agonist 6 6 Innovations in Gynecologic Cancer Care 5/12/2017 Molecular targets in ovarian cancer • EGFR • VEGF • PD‐L1 • MTOR • STAT‐3 • AMPK • Glucose metabolism 7 7 Innovations in Gynecologic Cancer Care 5/12/2017 Evidence to support core therapies in ovarian cancer • Pro‐oxidant cytotoxic single agent therapies • Botanical • Fungal • Hormones • Antioxidants • FDA approved drugs off label • Psychoneuroimmunologic 8 8 Innovations in Gynecologic Cancer Care 5/12/2017 Pro‐oxidant therapies single molecule therapies High dose parenteral ascorbate 25 – 100 grams/infusion Ma, Y., J. Chapman, et al. (2014). "High‐dose parenteral ascorbate enhanced chemosensitivity of ovarian cancer and reduced toxicity of chemotherapy." Sci Transl Med 6(222): 222ra218. 9 9 Innovations in Gynecologic Cancer Care 5/12/2017 IV Vitamin C therapy in ovarian cancer? Ma et al 2014 In vitro Depleted (ATM)/adenosine monophosphate–activated protein kinase (AMPK) pathway mTOR) inhibition and cytotoxic death in ovarian cancer cells. Animal models Parenteral ascorbate + Taxol/Carboplatin synergistically inhibited ovarian cancer in mouse models 10 10 Innovations in Gynecologic Cancer Care 5/12/2017 IV vitamin C RCT in women with ovarian cancer Reduced chemotherapy-associated toxicity in patients with ovarian cancer Improved PFS? Improved OS? 11 11 Innovations in Gynecologic Cancer Care 5/12/2017 Fig. 4. Reduction of toxicity and better PFS and OS in ovarian cancer patients after adding ascorbate to chemotherapy. Yan Ma et al., Sci Transl Med 2014;6:222ra18 12 Published by AAAS 12 Innovations in Gynecologic Cancer Care 5/12/2017 Botanical therapies used in the treatment of ovarian cancer • Epicatechins from green tea • Curcumin • Mistletoe • Indole‐3‐carbinol from broccoli • Quercetin • Bromelain • Artemisinin 13 13 Innovations in Gynecologic Cancer Care 5/12/2017 Green tea epicatechin 14 14 Innovations in Gynecologic Cancer Care 5/12/2017 From Lise Alschuler ND, FABNO 15 15 Innovations in Gynecologic Cancer Care 5/12/2017 Green tea epicatechin active in ovarian, breast and colon cancer. Trudel, D., D. P. Labbe, et al. (2013). "A two‐stage, single‐ arm, phase II study of EGCG‐enriched green tea drink as a maintenance therapy in women with advanced stage ovarian cancer." Gynecol Oncol 131(2): 357‐ 361. Trudel, D., D. P. Labbe, et al. (2012). "Green tea for ovarian cancer prevention and treatment: a systematic review of the in vitro, in vivo and epidemiological studies." Gynecol Oncol 126(3): 491‐498. 16 16 Innovations in Gynecologic Cancer Care 5/12/2017 Curcumin (no copyright) 17 17 Innovations in Gynecologic Cancer Care 5/12/2017 Turmeric, Curcumin Oral bioavailability of curcuminoids is low. IV curcumin is likely necessary for full anti‐cancer effect. Active across many solid tumor types. 18 18 Innovations in Gynecologic Cancer Care 5/12/2017 nuclear factor erythroid 2–related factor 2 (Nrf2) controls anti‐ oxidant response to ROS. 19 19 Innovations in Gynecologic Cancer Care 5/12/2017 Curcumin in vitro data Increases chemo and radiosensitivity (Saydmohammed, Joseph et al. 2010; Yallapu, Maher et al. 2010), STAT‐3 (Pan, Yang et al. 2008) AMPK (He, Wang et al. 2016) (Bondi, Emma et al. 2017) Induces apoptosis (Seo, Kim et al. 2016) Lowers drug resistance (Li, Zhou et al. 2016; Zhang, Liu et al. 2017) Lowers platinum resistance (Terlikowska, Witkowska et al. 2014) 20 20 Innovations in Gynecologic Cancer Care 5/12/2017 The adverse side effects of cancer treatment can often be attenuated with oral curcumin. 21 21 Innovations in Gynecologic Cancer Care 5/12/2017 Mistletoe lectins Widely used in Europe –SQ and IV improves QOL in ovarian cancer patients Mistletoe in vitro and animal data and clinical data (Schumacher, Feldhaus et al. 2000; Piao, Wang et al. 2004) 22 22 Innovations in Gynecologic Cancer Care 5/12/2017 Indole‐3‐carbinol Indole‐3‐carbinol In vitro data showing ovarian cancer sensitization to chemotherapy (Taylor‐Harding, Agadjanian et al. 2012). Vulvar cancer 200 mg bid po clinical trial (Naik et al2006) Naik, R., S. Nixon, et al. (2006). "A randomized phase II trial of indole‐3‐carbinol in the treatment of vulvar intraepithelial neoplasia." Int J Gynecol Cancer 16(2): 786‐790. Taylor‐Harding, B., H. Agadjanian, et al. (2012). "Indole‐3‐carbinol synergistically sensitizes ovarian cancer cells bortezomib treatment." Br J Cancer 106(2): 333‐343. 23 23 Innovations in Gynecologic Cancer Care 5/12/2017 Antioxidants Selenium Selenium supplementation reduces risk of ovarian cancer in African American women (Terry, Qin et al. 2017). We use it in BRCA positive patients Terry, P. D., B. Qin, et al. (2017). "Supplemental Selenium May Decrease Ovarian Cancer Risk in African‐American Women." J Nutr 147(4): 621‐627. 24 24 Innovations in Gynecologic Cancer Care 5/12/2017 Higher fungi Trametes versicolor Trametes versicolor: Over 50 trials in colorectal, a few on breast and lung cancer No clinical trials in ovarian cancer. NKCA predicts PFS in ovarian cancer patients (Garzetti, Cignitti et al. 1993) 25 25 Innovations in Gynecologic Cancer Care 5/12/2017 Turkey Tail: Trametes (Coriolus) versicolor, commonly called Turkey Tail is a small flexible polypore fungus that is an important part of the forest ecology as a recycler of dead and dying trees in forests throughout the world. In Japan, T. versicolor is know as kawaratake and in China, the fungus is called Yun Zhi or “cloud-like fungus” 26 26 Innovations in Gynecologic Cancer Care 5/12/2017 Hailing Lu, MD, PHD 27 27 Innovations in Gynecologic Cancer Care 5/12/2017 Strong PSK pre-clinical and clinical data Complex mechanism of action – activates innate immune system via multiple pathways Phase I trial of PSK or placebo + her2neu peptide vaccine + trastuzumab N=30 UW/Bastyr/NCCAM partnership (Disis/Salazar/Standish) NCT01922921 28 28 Innovations in Gynecologic Cancer Care 5/12/2017 Ferry DR et al Phase I clinical trial of the flavonoid quercetin: pharmacokinetics and evidence for in vivo tyrosine kinase inhibition. Clin Cancer Res. 1996 Apr;2(4):659-68. 29 29 Innovations in Gynecologic Cancer Care 5/12/2017 Quercetin (3,3',4',5,7‐pentahydroxyflavone) 1.Inhibits the growth of tumor cells 2.Prevents cancer metastasis and suppress cancer cell proliferation in animal models. 3.Inhibits signal transduction targets including tyrosine kinases, protein kinase C, and phosphatidyl inositol‐3 kinase 4.In one patient with ovarian cancer refractory to cisplatin, following two courses of quercetin (IV 420 mg/m2), the CA 125 had fallen from 295 to 55. 5. Can be safely administered by i.v. bolus at a dose injection (Ferry et al. 1996) BUT contraindicated with chemotherapy Li, N., C. Sun, et al. (2014). "Low concentration of quercetin antagonizes the cytotoxic effects of anti‐neoplastic drugs in ovarian cancer." PLoS One 9(7): e100314. 30 30 Innovations in Gynecologic Cancer Care 5/12/2017 Proteolytic enzyme therapy in evidence-based complementary oncology: fact or fiction? Integr Cancer Ther. 2008 Dec;7(4):311-6. Beuth J. • Anti-metastatic • Prevents and treats post-surgical fibrosis, • axillary webbing following