OncANP 2019

By Jacob Schor, ND, FABNO

 

The Eighth Annual Conference of the Oncology Association of Naturopathic Physicians (OncANP) was held in mid-February in San Diego.  The weather was terrible.  Dr. Jonathan Collin, the publisher of the Townsend Letter, had promised to attend but was forced to cancel his trip last second.  He had some excuse about snow and not being able to get his car out of the driveway.  I was disappointed both because I had looked forward to meeting him in person, but also because he could have written about the conference, leaving me off the hook.

Ethics panel members: (l-r) Heidi Lucas, Paul Reilly, Shani Fox, Michael Uzick, and Lise Alschuler encouraging Jacob Schor to sit down already.

Ethics panel members: (l-r) Heidi Lucas, Paul Reilly, Shani Fox, Michael Uzick, and Lise Alschuler encouraging Jacob Schor to sit down already.

It’s a challenge for me to write about the OncANP conference and be objective. I am tempted to be both hypercritical or too kind. This is my first year not serving on the group’s board of directors in a decade, though I remain on the speaker selection committee.  As I am still partly responsible for the conference, I am somewhat obligated to say nice things and hope more of you will attend next year.  

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This year’s lectures were all pretty decent.  Even the worst was not an outright stinker.  Many of the presentations were actually quite good, putting the mean quality level at way more than good. This  conservative evaluation may do little to convince those who didn’t attend to come next year.  Some people who don’t know me well may not realize how close to empty the cup of my life looks; I’m not prone to ebullient lecture evaluations. On a really good day, my opinions lean toward lukewarm.  When I talked to colleagues who were there, they employ superlatives, “the best lecture” or “the best conference ever”—those sorts of descriptions.  

But that’s life isn’t it? Not everyone sees things the same way.  One either learns to accept disagreement and a diversity of opinions or has to go through life thinking everyone around you is an idiot.  Remember that Dr. Collin, named my monthly column “The Curmudgeon’s Corner,” a name that some find appropriate.

OncANP requires our presenters to submit their lecture PowerPoints months before the conference. These go through peer review by conference committee members who then work with the speakers to improve their lectures.  The final presentations delivered at the conference are often significantly improved over the early drafts. 

One of our goals is to provide information that will be immediately relevant to attendees.  We ask ourselves whether hearing a speaker will make a difference “Monday morning” when back in the office.

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This proved an especially apt way to describe the material Lise Alschuler presented in her lecture on lifestyle modifications that lower breast cancer recurrence risk.  Sitting with my very first patient upon arrival back at our clinic, I paused partway through the visit and pulled up Dr. Alschuler’s lecture PowerPoint on my computer and went through it slide by slide with the patient.  I found this strategy effective and may make a habit of keeping Alschuler’s slides handy on my desktop. 

This modern business of computers and my ability to take home copies of all the conference lecture slides has been an adjustment.  I’m old school enough to believe that by listening hard I’ll remember all the important points; this idea is probably as antiquated as my paying for my landline telephone.  Lecturers now include so much information that it is not humanly possible for someone my age to keep track of it all.  Yet the search feature on the computer allows me to find the things I vaguely remember hearing and want to chew over more slowly.  In fact, let me share a few tidbits of info that I am still ruminating on.

Ralph Kleef, MD, from Vienna, Austria, shared information about his approach to immunotherapy, and in particular, about patients described as hyperprogressors.  These are the patients for whom the new immunotherapy drugs backfire in a terrible way, that is the PD-1 and PDL-1 inhibitor drugs trigger the tumors to grow incredibly fast.  Approximately 9% of patients respond this way.  Playing Russian roulette with a six-shot revolver has only slightly worse odds, as deciding to take these drugs.  Age seems to be the biggest predictor of hyperprogression; the older a patient is, the more likely this will happen.(1)  Kleef explained that hyperprogression is related to amplification of the MDM2 gene that regulates p53.  This gene’s action may increase five to forty-fold compared to normal.(2)  MDM2 encodes for a protein that suppresses p53 expression: “p53 is the guardian of the genome… is responsible for pausing replication so that DNA repair can take place, and if repair is not possible, p53 invokes apoptosis. MDM2 amplification deprives cancer cells of this safeguard.”(3) Amplification of MDM2 is a bad thing.

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We may soon be able to test for MDM2 amplification allowing prediction whether particular patients are at greater risk of hyperprogression on these immunotherapy treatments.

At the same time, we must acknowledge these immunotherapy drugs may work so well they seem miraculous. These good cases are associated with JAK3 activation.(4) We in the audience sat upright and paid close attention to every word Dr. Kleef said here, hoping to go home with the secret that might increase the odds of favorable responses.  Dr. Kleef listed several compounds that activate JAK3 including the following:

·       Curcumin,(5)

·       Parthenolides from feverfew,(6)

·       Guggulsterones from myrrh,(7)

·       Piceatannol (a relative of resveratrol),(8)  

·       Ursolic acid (a wax from apple skins and other fruits),(9)

·       Epimedium (Goat weed),(10)

·       Serenoa repens,(11)

·       Ginseng’s compound K,(12) and

·       Honokiol (magnolia extract).(13)

While thinking about PDL-1 inhibitors and how to increase the odds they will work, let me open Judy Fulop’s PowerPoint.   Dr. Fulop does yearly updates for us on biome and cancer.  The amount of newly published data that comes out each year on this topic is overwhelming; I feel guilty for originally asking Judy to volunteer to do this.

Oscar’s Fish Tacos in San Diego :  (l-r) Lise Alschuler, Marsha Pengruber, Tina Kaczor, (some guy at the next table), Jacob Schor, and Amy Rothenberg

Oscar’s Fish Tacos in San Diego:

(l-r) Lise Alschuler, Marsha Pengruber, Tina Kaczor, (some guy at the next table), Jacob Schor, and Amy Rothenberg

In January 2018, Gopalakrishnan reported on the oral and gut microbiomes of melanoma patients undergoing PD-1 immunotherapy and told us there are significant differences between responders and non-responders.  Analysis of fecal samples suggests more Ruminococcaceae in responding patients.  Giving fecal transplants from responding patients to germ-free mice enhanced their antitumor response to these drugs.(14) Also, this past year, Matson et al reported that patients with melanoma who responded to PDl-1 therapy had higher levels of Bifidobacterium longum, Collinsella aerofaciens, and Enterococcus faecium.(15)  In the near future we may be listing what bacteria we want in probiotic supplements for patients taking these drugs.

Knowledge on biome and cancer has reached the point that researchers claim they can distinguish between types of leukemia simply by looking at the patient’s gut biome.(16)

 

Dr. Fulop was able to take these ideas a step further this year.  While we can’t buy probiotics with the specified bacteria in them just yet, certain foods favor the growth of desirable bacteria.  Research tells us not just which general dietary patterns to favor but even specific foods that we should tell patients to eat. Laura Soldati et al compared the effect of various dietary types on gut microflora and suggested several specific supplements that encourage these population shifts including curcumin, green tea, quercetin, vitamins A, D, and E. In particular she emphasized the phenol- and polyphenol-containing foods.[xvii]

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Curcumin appears to shift the gut microbiome in a favora(17)ble direction.(18)

Gao suggested last year that gut bacteria may have such a large influence in part because they affect tryptophan metabolism and by extension melatonin levels in the body.(19)  New research this year confirmed that eating walnuts has a positive impact on the gut biome. Walnut consumption resulted in higher relative abundance of three bacteria of interest: Faecalibacterium, Roseburia, and Clostridium. (20)  While we have told cancer patients for years to eat more broccoli to increase sulforaphane in the body, in the past year research suggested that part of broccoli’s anticancer action is mediated by shifts in the gut biome.(21)

Tomato powder, (22) navy beans,(23) and black raspberries(24)  all alter the gut biome in ways that might explain their anticancer effects. Black raspberries look more intriguing as time goes on.(25)  The idea that the science has come so far that we can suggest specific foods to patients based on their mechanism of action mediating the biome is exciting.

Returning to Ralph Kleef’s lecture, he pointed out that the neutrophil-lymphocyte ratio (NLR) is also prognostic for immunotherapy responses. Dr. Jen Green brought this NLR business to our attention a few years back.(26) If NLR improves, patients are more likely to be positive responders to immunotherapy. High ratios though are bad news.  For example, an NLR ≥ 5 is associated with inferior overall survival in nivolumab-treated patients with lung cancer.(27)  A simple approach would be to try to improve the NLR ratio in patients being treated with immunotherapy drugs.

Many of our presenters now suggest particular supplements because they target specific pathways identified in individual tumors.  My colleague and regular conference roommate, Davis Lamson, convened a meeting one night in our bedroom to discuss creating a database that would match specific nutrients and supplements with specific pathways in tumors in a manner similar to the way new chemotherapy drugs are matched through tumor genetic testing via ‘liquid biopsies’.  This is both an exciting and contentious idea, so much so that I had better not take it up here.  Tumor cells evolve so quickly and work around blocked pathways so reliably that at this point in time, these targeted drugs have not been nearly as successful as was hoped.  The unknown is whether our natural therapies will fail in a similar manner or whether they will preserve drug sensitivity or hinder development of drug resistance in these patients.

Discussions like this might be too geeky for the general reader of the Townsend Letter.  But that’s part of the value of in-person meetings, they allow the opportunity to pursue such ideas and advance our understanding.

Immunotherapy seemed to be a recurring theme in this year’s lectures. Kleef employs a combination of hyperthermia and low-dosed immunotherapy drugs with his patients.  Gurdev Parmer, ND, FABNO from British Columbia uses a combination of hyperthermia and naturopathic therapies, including IV-C and mistletoe, with his patients. He reviewed his clinic’s patient outcome data collected over the past eight years. Kaplan-Meier charts of patient survivorship suggest that his patients do strikingly better than the SEER data would suggest they should, so much so that he is having difficulty finding a journal to publish this data. 

Dr. Jen Green departed from the immunotherapy theme to review how to prevent and treat cardiovascular injury in cancer patients. Between heart toxic chemotherapy agents (doxorubicin, cisplatin, and trastuzumab), hormone blocking therapies (tamoxifen, aromatase inhibitors, and androgen deprivation), and radiation therapies, it is surprising how little we talk about this.  For cancer survivors, heart problems are still their leading cause of morbidity and mortality.(28)  Not their cancers.  Yet we tend to focus on the cancer.  Thus Dr. Green’s lecture was a timely reminder to not overlook the hearts of our patients and instead to be vigilant to address their increased risks.  Dr. Green set a precedent by providing conference attendees a printable summary that some of us will keep on our desks as a cheat sheet. 

I remain disappointed that Dr. Collin couldn’t make it to OncANP this year as I would like to have seen how he reported on it.  I have touched on only a fraction of the ideas from a fraction of the lectures. That whole proverbial tip of the iceberg thing. I am hoping that both Dr. Collin and more of you join us at next year’s conference.

 

The 2020 OncANP Conference call for abstracts is posted here:  www.oncanp.org/events


References

1. JThorac Dis. 2018 Feb; 10(2):1124–1128. http://www.targetedonc.com/publications/targeted-therapy-news/2017/november-2017/immunotherapy-linked-to-hyperprogression-of-nsclc-and-other-cancers-; retrieved May 24, 2018.

2. Campiat S, et al. Hyperprogressive disease (HPD) is a new pattern of progression in cancer patients treated by anti-PD-1/PD-L1.Clin Cancer Res. 2016;23(8):1920-1928.

3. https://blogs.shu.edu/cancer/2017/03/22/hyperprogression-on-checkpoint-inhibition-immunotherapy/

4. Van Allen EM, et al Long-term Benefit of PD-L1 Blockade in Lung Cancer Associated with JAK3 Activation. Cancer Immunol Res. 2015 Aug;3(8):855-63.

5. Weissenberger J, et al. Curcumin (dietary) suppressed glioma growth in a mouse model by inhibition of the JAK1,2/STAT3 signaling pathway. Clin Cancer Res. 2010 Dec 1;16(23):5781-95.

6. Carlisi D, et al.  Parthenolide sensitizes hepatocellular carcinoma cells to trail by inducing the expression of death receptors through inhibitionof JAK2/STAT3 activation J Cell Physiol. 2011 Jun;226(6):1632-41.

7. Ahn KS, et al. Guggulsterone, a farnesoid X receptor antagonist, inhibits constitutive and inducible STAT3 activation through induction of a protein tyrosine phosphatase SHP-1.

Cancer Res. 2008 Jun 1;68(11):4406-15.

8. Takasawa R, Akahane H, Tanaka H. Piceatannol, a natural trans-stilbene compound, inhibits human glyoxalase I. Bioorg Med Chem Lett. 2017 Mar 1;27(5):1169-1174.

9. Pathak AK, et al. Ursolic acid inhibits STAT3 activation pathway leading to suppression of proliferation and chemosensitization of human multiple myeloma cells. Mol Cancer Res. 2007 Sep;5(9):943-55.

10. Chen M, et al. The Anticancer Properties of Herba Epimedii and Its Main Bioactive Componentsicariin and Icariside II. Nutrients. 2016 Sep 13;8(9). pii: E563.

11. Che Y, et al. Serenoa repens induces growth arrest and apoptosis of human multiple myeloma cells via inactivation of STAT 3 signaling. Oncol Rep. 2009 Aug;22(2):377-83.

12. Park S, et al. Inhibition of JAK1/STAT3 signaling mediates compound K-induced apoptosis in human multiple myeloma U266 cells. Food Chem Toxicol. 2011 Jun;49(6):1367-72.

13. Yu C, Zhang Q, Zhang HY. Targeting the intrinsic inflammatory pathway: honokiol exerts proapoptotic effects through STAT3 inhibition in transformed Barrett's cells. Am J Physiol Gastrointest Liver Physiol. 2012 Sep 1;303(5):G561-9.

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14. Gopalakrishnan V, et al.  Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients. Science. 2018 Jan 5;359(6371):97-103.

15. Matson V, et al The commensal microbiome is associated with anti-PD-1 efficacy in metastatic melanoma patients. Science. 2018 Jan 5;359(6371):104-108.

16. Rajagopala et al. Gastrointestinal microbial populations can distinguish pediatric and adolescent Acute Lymphoblastic Leukemia (ALL) at the time of disease diagnosis. BMC Genomics. 2016;17(1):635-

17. Soldati L, et al.  The influence of diet on anti-cancer immune responsiveness.  J Transl Med. 2018 Mar 20;16(1):75.

18. Zam W. Gut Microbiota as a Prospective Therapeutic Target for Curcumin: A Review of Mutual Influence. J Nutr Metab. 2018 Dec 16;2018:1367984.

19. Gao J, et al. Impact of the Gut Microbiota on Intestinal Immunity Mediated by Tryptophan Metabolism.  Front Cell Infect Microbiol. 2018 Feb 6;8:13.

20. Holscher HD, Guetterman HM, Swanson KS. Walnut Consumption Alters the Gastrointestinal Microbiota, Microbially Derived Secondary Bile Acids, and Health Markers in Healthy Adults: A Randomized Controlled Trial. J Nutr. 2018 Jun 1;148(6):861-867.

21. Kaczmarek JL, et al. Broccoli consumption affects the human gastrointestinal microbiota.  J Nutr Biochem. 2019 Jan;63:27-34..

22. Xia H, et al. Dietary Tomato Powder Inhibits High-Fat Diet-Promoted Hepatocellular Carcinoma with Alteration of Gut Microbiota in Mice Lacking Carotenoid Cleavage Enzymes. Cancer Prev Res (Phila). 2018 Dec;11(12):797-810.

23. Baxter BA, Oppel RC, Ryan EP. Navy Beans Impact the Stool Metabolome and Metabolic Pathways for Colon Health in Cancer Survivors. Nutrients. 2018 Dec 22;11(1). pii: E28.

24. Tu P, et al. Characterization of the Functional Changes in Mouse Gut Microbiome Associated with Increased Akkermansia muciniphila Population Modulated by Dietary Black Raspberries. ACS Omega. 2018 Sep 30;3(9):10927-10937.

25. Chen L, et al. Chemoprevention of colorectal cancer by black raspberry anthocyanin involved in modulation of gut microbiota and SFRP2 demethylation. Carcinogenesis. 2018 Mar 8;39(3):471-481.

26. Green J. Prognostic Role of Neutrophil-to-Lymphocyte Ratio in Cancer.  Natural Medicine Journal. December 2014.

27. Bagley SJ, et al. Pretreatment neutrophil-to-lymphocyte ratio as a marker of outcomes in nivolumab-treated patients with advanced non-small-cell lung cancer. Lung Cancer. 2017 Apr;106:1-7.

28. Moslehi J. The cardiovascular perils of cancer survivorship. NEJM. 2013;368:1055-6.