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Understanding Rhabdomyosarcoma

Natural Strategies in Collaborative Cancer Care

by John G. Connor, M.Ac., L.Ac.

edited by Barbara Connor, M.Ac., L.Ac.

April 6, 2011

 

Table of Contents

Introduction

 

Rhabdomyosarcoma, the most common soft-tissue sarcoma of childhood, results from the neoplastic transformation of cells of the skeletal muscle lineage. Rhabdomyosarcomas harbor a variety of genetic and molecular lesions that frequently include autocrine growth factor circuits along with alterations of oncosuppressor genes. (Nanni et al 2003)

Soft tissue sarcomas are a diverse group of rare tumors that comprise 1% of all cancers. For the majority of histological subtypes adjuvant chemotherapy is not of proven value, although there may be situations where it is advantageous. However, there are other subtypes, such as the Ewing's sarcoma family tumors, for which chemotherapy is an essential part of primary management and has definitely improved survival. Apart from Ewing's sarcoma family tumor and rhabdomyosarcoma, there is increasing specialization of chemotherapy according to histological subtype (Krikelis and Judson 2010)

Soft-tissue sarcomas (STS) include a spectrum of histologically and clinically different tumors. Patients with these tumors are typically relatively young and the course of disease is characterized by early metastasis as well as limited response to chemotherapy. However, a few subtypes, such as small round-cell tumors and rhabdomyosarcoma (other than pleomorphic), are considered chemotherapy sensitive.  (Kopp et al 2008)

 

Rhabdomyosarcoma (RMS) is one of the most common extracranial solid tumours in children. Embryonal and alveolar subtypes of RMS present completely different genetic abnormalities. Embryonal RMS (eRMS) is characterised by loss of heterozygosity on the short arm of chromosome 11 (11p15.5), suggesting inactivation of a tumour-suppressor gene. (Melcon & Codina 2007)  Rhabdomyosarcoma tumors are highly vascularized. (Wysocozynski et al 2010)   Bone marrow is a frequent site of tumor dissemination in RMS, especially in alveolar RMS. (Krskova et al 2010)

 

Individual studies estimate that as many as 69% of US cancer patients employ some type of complementary and alternative medicine, 76% of patients in a study of Midwestern cancer patients and 95% of radiation oncology patients in another study.  (Wargovich et al 2010)

 

Barbara and I feel that the emerging concept and practice of targeted therapies which have a high specificity toward tumor cells provides a broader therapeutic window with less toxicity than the current chemotherapeutic agents. They are also often useful in combination with cytotoxic chemotherapy or radiation to produce additive or synergistic anticancer activity because their toxicity profiles often do not overlap with traditional cytotoxic chemotherapy. Targeted therapies represent a new and promising approach to cancer therapy, one that is already leading to beneficial clinical effects. There are multiple types of targeted therapies available, including monoclonal antibodies, receptor tyrosine kinase inhibitors, and growth factor receptor inhibitors.

 

The wonderful thing about botanicals and nutritives is that they target many of the same growth factors, receptors and pathways as conventional drugs and chemos but in a gentler and less toxic way thereby allowing for decreased dosages in the more toxic chemos and drugs. One of the characteristics of plants is that they are pleiotrophic, i.e., they exert multiple effects. Therefore botanicals and herbs by their very nature not only enhance the effectiveness of chemos and drugs but they can reduce or eliminate many of their unwanted side effects.

 

There is an ever growing interest in treatment with natural compounds as an adjuvant cancer therapy along with conventional cancer therapy. (Virk-Baker et al 2010) For example the combination of a natural VEGF inhibitor along with lower doses of a pharmacological agent may prove helpful in reducing the unwanted side effects of chemotherapy. (Wargovich et al 2010)

 

Natural Strategies in Collaborative Cancer Care

 

The following is a list of natural strategies we employ and the issues we address in our approach to integrative cancer care:

 

 

Examples of Natural Compounds Suppressive Against Rhabdomyosarcoma

 

  1. Betulinic acid - Our data show that induction of apoptosis and inhibition of hedgehog signalling are important features of the anti-tumourigenic effect of Betulinic acid in RMS and advices this compound for the use in a multimodal therapy of this highly aggressive paediatric tumour. (Eichenmuller et al 2010) 

 

  1. Curcumin has been shown to inhibit the growth of rhabdomyosarcoma cells.  The data suggest that curcumin may execute its anticancer activity primarily by blocking mTOR-mediated signaling pathways in the tumor cells. (Beevers et al 2006)

 

  1. Resveratrol - Another study showed that resveratrol exerts a strong inhibition of rhabdomyosarcoma cell proliferation in part by arresting cells in S/G2 phase of the cell cycle. (Chow et al 2005)

 

  1. Resveratrol - It has also been found that resveratrol causes COX-2- and p53-dependent apoptosis (programmed cell death) in head and neck squamous cell cancer cells. (Lin et al 2008)

Examples of Biomarkers in Rhabdomyosarcoma

 

  1. An increased expression of p53, p21(WAF1), and Bax protein was observed after treatment with MI-63 in Rhabdomyosarcoma (RMS) cells with wild-type p53, and apoptosis was confirmed by cleaved PARP and caspase-3 expression. (Canner et al 2009)

 

  1. EGFR, PDGFR-alpha, PDGFR-beta, Bcl-2, and Bax are frequently expressed in human rhabdomyosarcoma (RMS) tissue and may represent new therapeutic targets. Absence of PDGFR-alpha and the presence of Bax are associated with a longer median OS in patients with RMS. Targeting these molecules may be a successful therapeutic strategy.  (Miyachi et al 2009)

 

  1. C-kit – is a type III receptor tyrosine kinase.  It is found that interactions between kit and its ligand, SCF (stem cell factor), are important in the development and maintenance of hematopoietic cells, melanocytes, germ cells, and the interstitial cells.  The c-Kit that encodes the receptor for stem cell factor plays a significant role in signal transduction as well as in metastasis.  (Bagchi and Preuss 2005)  Inhibitors of kit tyrosine activity could have therapeutic efficacy.

 

  1. mdm2 – The p53 tumor suppressor gene is inactivated in human tumors by several distinct mechanisms. The best characterized inactivation mechanisms are: (i) gene mutation; (ii) p53 protein association with viral proteins; (iii) p53 protein association with the MDM2 cellular oncoprotein. The MDM2 gene has been shown to be abnormally up-regulated in human tumors and tumor cell lines by gene amplification.  Gene amplification was observed in 19 tumor types, with the highest frequency observed in soft tissue tumors (20%), osteosarcomas (16%) and esophageal carcinomas (13%). (Momand et al 1998)

 

  1. All mdx and Sgca(-/-) RMS analyzed had increased expression of p53 and murine double minute (mdm)2 protein and contained missense p53 mutations previously identified in human cancers. (Fernandez et al 2010)

 

  1. Interruption of the role of p53s as a tumour suppressor by MDM2 may be one of the mechanisms by which cancer cells evade current therapy.  (Canner et al 2009)

 

  1.  MDR-1 (Multiple Drug Resistance – 1) - The evaluation of DNA ploidy, p53, MIB1 and MDR-1 expression could be used for subtyping of orbital rhabdomyosarcoma (RMS) into two prognostically different subcategories, respectively RMS responder to the therapy, with favourable clinical outcome, and RMS with a worse prognosis, requiring more aggressive therapeutic protocols. (Staibano et al 2004)

 

  1. p21 - In embryonal rhabdomyosarcomas, p21 may be involved in inhibition of myogenic precursor cell proliferation and differentiation. (Inoue and Wu 2006)

 

  1. p 53 - Seventy to eighty percent of rhabdomyosarcoma (RMS) tumors retain wild-type p53. The tumor suppressor p53 plays a central role in inducing cell cycle arrest or apoptosis in response to various stresses. (Miyachi et al 2009)

 

  1. EGFR, PDGFR-alpha, PDGFR-beta, Bcl-2, and Bax are frequently expressed in human rhabdomyosarcoma (RMS) tissue and may represent new therapeutic targets. Absence of PDGFR-alpha and the presence of Bax are associated with a longer median OS in patients with RMS. Targeting these molecules may be a successful therapeutic strategy.  (Miyachi et al 2009)

 

  1. PDGF - Increased transcriptional levels of PDGF receptors and insulin-like growth factor are associated with decreased survival in rhabdomyosarcomas. Dual blockade of these growth-factor-signaling pathways may be a valuable strategy in preclinical therapeutic studies. (Blandford et al 2006)

 

  1. PPAR alpha – Bezafibrate induced myotoxicity in human rhabdomyosarcoma cells via PPAR alpha upregulation. (Zhao et al 2010)

 

  1. Urokinase-type plasminogen activator (uPA) binds to its receptor, uPAR, on the surface of cancer cells, leading to the formation of plasmin. Rhabdomyosarcoma (RMS) cell lines secrete high levels of insulin-like growth factor II (IGF-II), suggesting autocrine IGFs play a major role in the unregulated growth and metastasis of RMS. In vitro, IGF-II and IGF-I increased migration of RD cells. (Gallicchio et al 2003)

 

  1. VEGF – vascular endothelial growth factor – can promote the growth of rhabdomyosarcoma cells through VEGFR1. (Li et al 2006)

 

Examples of Chemotherapeutic Agents Used in Rhabdomyosarcoma

 

Avastin (Bevacizumab) - Bevacizumab seems to have a good acute safety profile and some antitumor activity in heavily pretreated children and young adults with recurrent solid tumors. (Benesch et al 2008)

 

Avastin - VEGF can promote the growth of rhabdomyosarcoma cells through VEGFR1, and this effect can be blocked by Avastin. (Li et al 2006)

Cyclophosphamide - (CTX) (Cytoxan, Neosar)  An alkylating agent which nterferes with DNA base pairing leading to strand breaks.

Doxorubicin – Anthracycline, Adriamycin, Antibiotic, antineoplastic.  Mutated p53 correlates with poor response to DOX in breast cancer.  High expression of TOPO2A and low expression of PGP have been associated with benefit from anthracycline-based therapy. (Target Now)

Etoposide - Oral maintenance therapy seems to be a promising option for patients with RMS-like stage IV tumors. (Klingebiel et al 2008)

Etoposide - Our findings specifically highlight the topoisomerase poison 9-amino-DACA, its 5-methylsulphone derivative, AS-DACA, and the bis(phenazine-1-carboxamide) transcription inhibitor MLN944/XR5944, currently in phase I trial, as candidates for further research into new agents for the treatment of RMS. (Wolf et al 2009)

Irinotecan - CPT-11 Camptotheca acuminate (Camptosar). A Topoisomerase I inhibitor. It is effective in those who test negative for UGT1A1 mutation. If homozygous for the UGT1A1 allele it increases toxicity.  UGT1A and Thymidylate Synthase predict toxicity in colorectal cancer patients on CPT-11 & 5FU. (Martinez-Balibrea 2010)

 

Individuals who are homozygous for the UGT1A1*28 allele (7 repeats) may exhibit reduced degradation of SN-38 and increased probability of severe toxicities. (Deeken et al 2008)  SN-38 is an active metabolite of irinotecan and is responsible for the pharmacological and toxic effect of irinotecan.  SN-38 is glucoronidated by Uridine diphosphate-glucoruonyl transferase enzymes (UGT), predominantly by UGT1A1 isoenzyme. (Genelex provides a cheek swab collection kit by mail.)

 

MI-63 – is a novel small-molecule inhibitor targets MDM2 and induces apoptosis in embryonal and alveolar rhabdomyosarcoma cells with wild-type p53. MI-63 is a potent therapeutic agent for RMS cells expressing wild-type p53 protein. (Canner et al 2009)

 

Rapamycin inhibited the basal or insulin-like growth factor 1 (IGF-1)-induced motility of human Ewing sarcoma (Rh1) and rhabdomyosarcoma (Rh30) cells. The results suggest that rapamycin inhibits cell motility, in part by targeting PP2A-Erk1/2 pathway. (Liu et al 2010)

 

Trabectedin - is a tetrahydroisoquinoline molecule that was originally derived from a marine organism. It is indicated in the EU and many other countries for use in patients with advanced soft-tissue sarcoma (STS) who have progressed despite receiving previous treatment with anthracyclines and ifosamide or in those who are unable to receive these agents. Results to date indicate that trabectedin is a valuable addition to the group of second-line antineoplastic agents available for the treatment of advanced, recurrent STS.  (Carter & Keam 2010)

 

Trabectedin has dual effects in liposarcoma: in addition to direct growth inhibition, it affects the tumor microenvironment by reducing the production of key inflammatory mediators. (Germano et al 2010)

 

Vincristine -Vinca rosea, Madagascar periwinkle, (Oncovin), Binds to tubulin protein preventing cell from undergoing cell division.  They inhibit cell mitosis by binding to the protein tubulin in the mitotic spindle preventing polymerization into the microtubules

 

Examples of Natural Compounds that Target Growth Factors and Genes Involved in RMS

 

In general, natural compounds selectively target cancer cells as well as exert multiple effects.  Tumor cells are generally more sensitive to the growth depression caused by natural compounds than are normal cells. For example, EGCG has been shown to induce a dose dependent inhibition of cell growth in human osteosarcoma cells but did not influence normal rat osteoblasts. Some dietary components may have multiple molecular targets that can affect different phases of the cell cycle.  For example resveratrol inhibits cell cycle progression at different stages depending on the cell examined; and sulforaphane can modulate different phases of the cell cycle. (Davis 2010)

 

AP-1 (Activator Protein 1) -  is a transcription factor which regulates gene expression in response to a variety of stimuli, including cytokines, growth factors, stress, and bacterial and viral infections. AP-1 controls a number of cellular processes including differentiation, proliferation, and apoptosis.

 

Altered AP-1 activity that leads to the down-regulation of the Wnt pathway may contribute to the inhibition of myogenic differentiation and resistance to apoptosis in embryonal rhabdomyosarcoma cases. (Singh et al 2010)

 

Examples of Natural Compounds that inhibit AP-1

  1. Ganoderma lucidum (Reishi) – (Weng et al 2008)
  2. Pterostilbene – inhibits AP-1 (Pan et al 2009)

 

Bcl-2 – is an NF-κB regulated gene that functions by blocking the apoptosis pathway, thus immortalizing cancer cells. It has been suggested that Bcl-2 over expression results in the up regulation of VEGF expression with increased neoangiogenesis in human cancer xenografts.

 

Elevated Bcl-2 is an indication that someone is going to be resistant to chemotherapy.  Veripath lab tests for Bcl-2.

 

EGFR, PDGFR-alpha, PDGFR-beta, Bcl-2, and Bax are frequently expressed in human rhabdomyosarcoma (RMS) tissue and may represent new therapeutic targets (Miyachi et al 2009)

 

Natural Compounds that Inhibit Bcl-2

  1. Andrographolide (Zhou et al 2006) – Andrographis
  2. Mistletoe – (Choi et al 2004)
  3. OPCs – grape seed extract – (Bagchi et al 2000)
  4. Oridonin (Rabdosia rubescens) – (Ikezoe et al 2005) (Liu et al 2005)

 

COX-2 (Cyclooxygenase-2) - is up-regulated in practically all cancers (75%).  It is induced by phorbol esters, cytokines and growth factors, including TGF-beta-1 and bFGF.  COX-2 is a potent inducer of angiogenesis by inducing angiogenic factors. Most common cancers with altered (amplified) COX-2 expression include: prostate, colon, breast, cervical, brain, gastric, pancreatic, lung, head and neck, kidney and bladder.

 

Celecoxib inhibits STAT3 phosphorylation and suppresses cell migration and colony forming ability in rhabdomyosarcoma cells. Our results suggest that, though known more commonly as a cyclooxygenase-2 (COX-2) inhibitor, celecoxib could act through the STAT3 pathway as well. More importantly, its effect on cell migration and clonogenic colony forming ability make it a potentially useful therapeutic agent for rhabdomyosarcoma, especially in metastatic disease whose clinical outcome is marginal at best with current therapies. (Reed et al 2011)

 

Aspirin and rofecoxib (non-selective and selective COX-2 inhibitor, respectively) each abolished fibronectin-associated induction of MMP-2 and induced dose-dependent reductions in cellular invasiveness. These data implicated a role for inducible COX-2 and PGE(2) in the regulation of rhabdomyosarcoma cellular invasiveness and MMP-2 activity. (Ito et al 2004)

 

Examples of Natural Compounds that Down-Regulate COX-2:

1.       Panax notoginseng (Son et al 2009)

2.      Parthenolide (Weng et al 2009)

3.       Pterostilbene (Pan et al 2008)

4.       Quercetin (Lee et al 2010) (Turner et al 2009) (Warren et al 2009)

5.       Resveratrol (Kang et al 2009)

 

EGFR – (Epidermal Growth Factor Receptor) - Pathways that affect EGF inhibition are mTOR, PTEN, NF-kappaB, LOX, COX-2 etc.  The EGFR-1 signaling pathway is a very important pathway and is involved in many cancers.  It is a very important target for dietary, botanical and nutritional medicine as well as the drug Metformin.

 

The combination of EGFR and fibrillin-2 was able to detect embryonal rhabdomyosarcoma with a specificity of 76% and sensitivity of 90%. (Grass et al 2009)

EGFR, PDGFR-alpha, PDGFR-beta, Bcl-2, and Bax are frequently expressed in human rhabdomyosarcoma (RMS) tissue and may represent new therapeutic targets.  (Miyachi et al 2009)

 

Examples of Natural compounds shown to block EGF receptor activation and its downstream effectors include:

1.      Curcumin – curcumin has the potential as the leading compound for anti-cancer proliferation and invasion in oral cancer treatment, and cdc27, EGFR substrate 15, PPAR-alpha and H2A histone may play an important role among this multiple anticancer-targeting ability. (Chen et al 2011)

2.       Curcumin – Based on our findings, we hypothesize that accurate definition of the EGFR status could improve prognostic stratification and we suggest a possible role for EGFR-directed therapies in PC patients. Our results suggest that curcumin is an interesting chemopreventive agent for early stage prostate cancer. (Teitan et al 2011)

3.      Vitamin D-3 – in colon cancer. (Tong et al 1999) and in some breast cancer cells (McGaffin et al 2004)

GJIC – (Gap Junction Inter-Cellular Communication) is about how well immune cells communicate with each other.  Cancer cells interrupt them.  In cancer disruptions of GJIC are often induced by H-ras by the activation of p38.  (H-ras is an oncogene highly involved in the initiation of cancer.)

Rhabdomyosarcoma (RD) cells express low levels of the gap junction protein connexin 43 (Cx43), and its mRNA, and display very weak gap junctional intercellular communication (GJIC) as detected by Cx43 immunofluorescence, slot-blot and dye-transfer methods. These cells grow rapidly and show aberrant and incomplete myogenic differentiation. (Lin et al 1995)

 Examples of Natural Compounds that Enhance or Modulate GJIC

1.      Green Tea Extract – GTE may inhibit tumor promotion by enhancing GJIC and that the most active components are the catechin gallates. (Sigler & Ruch 1993)

2.      Sulforaphane (SFN) - Chinese cabbage extracts and SFN were able to prevent the inhibition of GJIC through the blocking of Cx43 phosphorylaton and inactivation of ERK 1/2 and p38 MAP kinase. The results suggest that cruciferous vegetables and their components, SFN, may exert the anticancer effect by targeting the GJIC as a functional dietary chemopreventive agent. (Hwang et al 2005)

Comprehensive Cancer Care Consultations

 

Barbara & I have been working in the integrative oncology setting for many years and have been collaborating closely with Donald Yance for 6 years.  We are graduates of both his Level One and Level Two Professional Clinical Trainings - Fundamentals of the ETMS (Eclectic Triphasic Medical System) and Advanced Clinical Applications of the ETMS in Cancer Therapies.

 

Our cancer protocols are designed to work synergistically with targeted individualized medical treatment plans and emphasize the practice of healthy medicine aimed at the root source of ill-health.  Our primary focus is to build your immune system, enhance your vitality, and to bring about harmony and balance throughout your body.  The botanicals and nutrients will target a multitude of cancer pathways generally and specifically in each case.

 

Using chemo-sensitivity screening and tumor marker testing we will be identifying what are the most appropriate chemos or drugs to use which will have the greatest impact on the cancer and at the same time have the least negative impact on your health. If you need to undergo chemotherapy or radiation we will provide you with specific protocols to help alleviate the side effects as well as specific protocols to help enhance the effects of the chemos.

 

If you are interested in finding out more about how we work or if you would like to set up a phone consult please phone us at 919-309-7753 or email us at johnandbarbaraconnor@me.com.

References

 

1.       Bagchi, Debasis & Harry G. Preuss, Phytopharmaceuticals in Cancer Chemoprevention, CRC Press, Boca Raton, 2005

 

2.       Beckett, Geoffrey, Simon Walker, Peter Rae & Peter Ashby, Lecture Notes – Clinical Biochemistry, 8th edition, Wiley-Blackwell, Oxford,  2010

 

3.       Boik, John, Natural Compounds in Cancer Therapy, Oregon Medical Press, Princeton, MN, 2001

 

4.       Boik, John, Cancer & Natural Medicine, A Textbook of Basic Science and Clinical Research, Oregon Medical Press, Princeton, MN, 1996

 

5.       Chernecky, Cynthia C, and Barbara J. Berger, Laboratory Tests and Diagnostic Procedures, Saunders, St. Louis, 2008

 

6.       Davis, Cindy D, Nancy Emenaker and John Milner, “Cellular Proliferation, Apoptosis and Angiogenesis: Molecular Targets for Nutritional Preemption of Cancer, Seminars in Oncology, Vol 37, No. 3, June 2010, pp 243-257

 

7.       Gullet, Norleena P, Ruhul Arnin, Soley Bayraktar, et al, “Cancer Prevention With Natural Compounds”, Seminars in Oncology, Vol 37, No 3, June 2010, pp 258-281

 

8.       Heber, David, Editor-in –Chief, Nutritional Oncology, Second Edition, Academic Press, London, 2006

 

9.       McKenna, Dennis J., PhD,  Kenneth Hones & Kerry Hughes, Botanical Medicines, The Desk Reference for Major Herbal Supplements, Second Edition, The Haworth Herbal Press, New York, 2002

 

10.   Mills, Simon and Kerry Bone, Principles and Practice of Phytotherapy, Churchill Livingstone, Edinburgh, 2000

 

11.   Neal, Michael J., Medical Pharmacology at a Glance, Sixth edition, Wiley-Blackwell, Oxford, 2009

 

12.   Stargrove, Mitchell, Jonathan Treasure & Dwight L. McKee, Herb, Nutrient, and Drug Interactions, Mosby Elsevier, St. Louis,  2008

 

13.   Weiss, Rudolf, MD & Volker Fintelmann, MF, Herbal Medicine, Thieme, New York, 2000

 

14.   Yance, Donald, “Donald Yance’s Eclectic Triphasic Medical System (ETMS): An Integrative Wholistic Approach to Treating and Preventing Cancer”, (Monograph) 2010

 

15.   Yance, Donald, Herbal Medicine, Healing & Cancer, Keats Publishing, Lincolnwood (Chicago) IL, 1999

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