+Introduction to the Biology of Functions and its application to Cancer

By:Jean Claude Lapraz, MDKamyar M. Hedayat, MD

+Cancer: Introduction

Cancer is a deregulation of cell growth

Modern research has focused on the role of oncogenes and proto-oncogenes in the etiology of tumors

However, oncogenes and proto-oncogenes Require some type of stimulation (i.e. viral infections,

environmental toxins), thus the detection of oncogenes alone is not sufficient to predict risk of cancer in all cases

The degree and duration of their expression is managed by the endocrine system and modulated by the immune and neurovegetative systems and this cannot be determined by current binary lab testing services

+Presentation of Cancer

Regardless of whether a cancer is slow or fast growing, there is a time period in which there is dysplastic then dedifferentiated cell growth before a diagnosis of cancer is made due to Palpation of a sufficient number of cancerous cells Mass effect from a space-occupying lesion Disruption of cellular metabolism

By the time many cancers are detected by the above noted methods, it is often in an advanced state

The ability to detect a cancer in a less advanced state would be invaluable

+Cancer: Screening Tests

The efficacy of common screening tests to diagnosis metastatic cancers, such as yearly mammograms and PSA testing have come in to question due to Detection and biopsy of benign masses1,2

Treatment of tumors which may have spontaneously regressed3

Inability to anticipate aggressive tumors which grow in a short period of time1,2

1. Esserman L, Shieh Y, Thompson I. Rethinking screening for breast cancer and prostate cancer. JAMA. Oct 21 2009;302(15):1685-1692.

2. Woolf SH. The accuracy and effectiveness of routine population screening with mammography, prostate-specific antigen, and prenatal ultrasound: a review of published scientific evidence. Int J Technol Assess Health Care. Summer 2001;17(3):275-304.

3. Zahl PH, Maehlen J, Welch HG. The natural history of invasive breast cancers detected by screening mammography. Arch Intern Med. Nov 24 2008;168(21):2311-2316.

+Cancer: Prevention and Risk Assessment Large scale nutritional interventions aimed at preventing

cancer have been equivocal, or, even showed an increased rates of cancer Diets rich in fruits and vegetables: equivocal1

High doses of antioxidants: increased incidence of lung cancer2

The short-coming in these studies was two Inappropriate or lack of stratification of subjects based on

metabolic type: catabolic vs. anabolic vs. mixed Inappropriate understanding of the quality and types of

supplements

1. Hung HC, Joshipura KJ, Jiang R, et al. Fruit and vegetable intake and risk of major chronic disease. J Natl Cancer Inst. Nov 3 2004;96(21):1577-1584.

2. The effect of vitamin E and beta carotene on the incidence of lung cancer and other cancers in male smokers. The Alpha-Tocopherol, Beta Carotene Cancer Prevention Study Group. N Engl J Med. Apr 14 1994;330(15):1029-1

+Short comings in Cancer research

Modern cancer research has been impressive in elucidating the genetic, cellular, and sub-cellular mechanisms of cancer, however, two issues continue to hamper cancer treatment The ability to account for individual metabolic, endocrine

and genetic factors in cancer risk assessment and treatment

The ability to account for multiple risk factors simultaneously in a dynamic, quantitative and qualitative manner in order to differentiate

What is needed is a functional, dynamic testing system to both anticipate, determine the causes of, and witness the efficacy of treatment of cancers

+Laboratory studies

• Classical lab data is based on binary considerations: • disease vs. no disease• normal vs. abnormal value

• In many instances, patients have normal lab values but exhibit symptoms or physiological irregularities consistent with a sub-optimal state of health.

• Binary considerations cannot be applied with any real assurance of its functional relevance to a system as complex as the human body.

+Laboratory studies

• Biological systems, like social interactions are complex, multi-tiered, dynamic interrelated and integrated systems Yeast Protein Interaction

Network

Bader and Hogue (2002) Nature

Pattern of cellular phone calls between friends

+Integrated systems

• Objective quantitative data (laboratory values) are required to assess the organism

• However, the true utility of binary values is when they are able to provide functional descriptions of quantitative and qualitative activity: • Within a particular unit of activity• Of one unit to another,• Of the system as a whole

• Only then can a truly dynamic and individualized assessment of the patient occur

+Laboratory studies

• The endocrine system, as the manager of the metabolic activity of the body is the ideal object of evaluation

• Serum levels of hormones only reflect quantitative organ output, not functional activity, which can be affected by:• Hormone receptor binding1

• Intracellular messenger activity1

• Epigenetic changes2 • Heavy metal toxicity3, etc.

• Moreover, serum levels of hormones do not reflect the degree of stimulation needed or the metabolic costs incurred in producing a particular hormone

1) Raison CL, Miller AH. When not enough is too much: the role of insufficient glucocorticoid signaling in the pathophysiology of stress-related disorders. Am J Psychiatry. Sep 2003;160(9):1554-1565

2) Chiam K, Tilley WD, Butler LM, Bianco-Miotto T. The dynamic and static modification of the epigenome by hormones: A role in the developmental origin of hormone related cancers. Biochim Biophys Acta. Apr 2009;1795(2):104-109.

3) Gerhard I, Waibel S, Daniel V, Runnebaum B. Impact of heavy metals on hormonal and immunological factors in women with repeated miscarriages. Hum Reprod Update. May-Jun 1998;4(3):301-309.

+Laboratory studies

• The ideal system of measurement of biological processes thus should examine the metabolic products of hormonal management of cellular activity

• In conclusion, the ideal laboratory system must• Reflect the complex, integrated and dynamic nature of

biological systems• Describe the functionality of the system in its

• Qualitative function • Quantitative function• Individual unit, relative to other units and as a whole

• Assess the organism at the metabolic and interstitial level

+Biology of functions

• Biology of Functions (BoF) quantifies functional abilities of the organism, before, during and after the effects of adaptation to stressors. Because functionality is dynamic, a dynamic, integrated and evolutionary methodology must be used instead of static lab values

• BoF is based on a number of specific indices defined by mathematical relations between commonly used blood analysis data

• The algorithms that permit the calculation of these indices are based on the physiological relations that exist between the direct or indirect products of hormonal activity: cells, hormones or enzymes (eosinophils, monocytes, lactate dehydrogenase, for example).

+Biology of functions

• These relations allow one to visualize the functioning of the organism at every level: • maintenance of homeostasis• Adaptation to stressors• Recovery after aggression• Immunity, etc.

• Each function is quantified by an index, specified by a level of activity. The index expresses the actual activity of that function, both in and of itself and in relation to the metabolic and tissue needs of the organism.

• The whole set of indices gives an evolutionary assessment of an individual body’s functionality, system by system, organ by organ.

+Biology of Functions and Cancer

With respect to cancer, the BoF accounts for individual factors that contribute to dedifferentiated cell growth: Endocrine: TRH, Estrogen, Testosterone, Insulin, etc. Neurovegetative: Norepinephrine, histamine, serotonin, etc. Immunologic: Interleukins, inflammatory activity

As well as cumulative effects of these factors on Metabolism: Active and passive membrane permeability,

mitochondria strain, Redox status, etc. Cellular function: nucleocytoplasmic cytopathogenecity,

membrane fracture, membrane expansion, apoptosis, necrosis

+Biology of Functions and Cancer

By assessing the current, functional activity of the organism, the Biology of Functions is able to assess multiple risk factors in relationship to each other Carcinogenesis Index: The degree of dysplastic activity Cancerous Index: The relative degree of endocrino-

metabolic factors which are propitious to cancerous activity Expansiveness index no.2: the relative risk of anarchic

cellular development due to adaptive phenomenon Active Carcinogenesis: The actual functional rate of cancer

cell growth after assessing for the rate of pathological cell death from apoptosis or necrosis

Active effective carcinogenesis: Witnesses the insufficiency of the organism’s defenses in the face of cancer over activity

Carcinogenesis expansion: the degree and speed of a cancer’s evolution

+Biology of functions

• SUMMARY: Biology of Functions allows one to determine: • Pathogenic tendencies of the organism • The stage of development and the degree of severity of a

potential pathology (i.e. cancer, cardiac disease, degenerative neurological disease)

• Biology of functions can be used as a tool to track• the natural development of pathology• To derive a rational therapeutic treatment• To evaluate the efficacy of the treatment over time

+CASE STUDY

GLIOBLASTOMA MULTIFORME REFRACTORY TO RADIOTHERAPY AND TEMOZOLOMIDE IN A 9 YEAR OLD FEMALE

+Case History

9 year old female was diagnosed with a right thalamic tumor in 1/07. She underwent resection with post-operative morbidities including intracerebral hemorrhage.

Tumor size was noted to be increasing on a follow up MRI on 8/08

A repeat MRI on 10/31/08 indicated continued growth of the lesion.

Partial resection was performed and a pathological assessment determined the tumor to be a glioblastoma multiforme

+Case History

Patient underwent focal radiotherapy and daily Temozolomide in early 2009, completed 3/09

Follow up MRI 4/09 revealed progressive local disease in the resection cavity, which was not considered to be resectable

Patient sought a second opinion for assessment and treatment using the endobiogenic system and the biology of functions

Initial assessment performed 4/09, with subsequent follow up on 10/09.

Follow up MRI’s on 8/09 and 11/09 revealed stable tumor size with no further growth or metastasis

+Initial Assessment: 4/09

The biology of functions revealed an encapsulated adenoid type growth Fibrosis index: 9.82 (6-8) Adenoid index: 421 (10-30)

The cancer was quite active, though the cancer was characterized as a relatively slow-developing growth and not extremely anarchic in its growth pattern and insufficient apoptosis Active cancer index: 1,831 (0.01-4.8) Cancer expansion index: 0.004 (0.02-3.08) Expansivity index no.2: 6.47 (1-4) Apoptosis index: 0.15 (0.9-1.4)

+Initial assessment: Thyrotropic factors The hypothalamic-metabolic factors, namely TRH and

cellular metabolic factors were found to play the most important role in the patient’s cancer growth.

We have noted that in brain cancers in general, and pediatric brain cancers in particular, that TRH plays a very important role in the etiology and growth of the cancer

TRH-influenced factors DNA fracture: 10.27 (0.5-1.5) Global TRH adaptation index: 18.6 (3-9) Pro-inflammatory index: 0.44 (0.1-0.4)

+Initial Assessment: Metabolic factors The cancer had a catabolic, acidic quality with a high

degree of intracellular communication: Active cellular permeability: 1,482 (6-9)

With poor passive permeability, contributing to the high degree of nucleocytoplasmic pathogenicity and toxin accumulation within the cell, and excessive nutrient oxidation with free radical accumulation Passive cellular permeability: 3.06 (4-9) Nucleocytoplasmic pathogenicity: 37 (0.8-1.5) Harmful free radical index: 122 (2-6)

+Initial Assessment:Other Factors

There was a significant elevation in androgenic activity, as well as an up-regulation of both peripheral androgen and estrogen receptors Androgen index: 0.52 (0.05-0.09) Androgen index comparative: 0.31 (0.1-0.3) Quantitative estrogen organo-tissular yield: 23,635 (67-

1006)

Growth factors also played an important role Metabolic Growth Index: 16.53 (2-6) Membrane Expansion: 0.48 (0.08-0.16)

+Initial Treatment

Medicinal Plants: Prunus amygdalis (Sweet almond): reduces peripheral

growth factors Quercus pedunculatus (English oak): Glucocorticoid activity

to reduce tumor size Tilia tomentosa (Silver linden): reduces TRH activity, anti-

inflammatory, neuro-calmative, liver regenerative Juglans regia (Black walnut): exo- and endocrine pancreatic

activity, reducing TRH and para-sympathetic stimulation of pancreas; stimulates hepatic macrophages and plasmocytes

Brassica napus (Cabbage): blocks TSH stimulation of thyroxine production and release, anti-inflammatory

Ilex acquafolium (Holly tree): anti-fibrotic

+Initial Treatment Supplements:

Vitamin C 6gm/d + Vitamin K 2, K3: anti-tumoral activity in conjunction with Vitamin C1

Melatonin2 10 gm qHS to reduce estrogen receptors2, Leutinizing hormone3 and for its anti-tumoral activity4

Exocrine digestive enzymes: to reduce parasympathetic activity

Diet: Dietary changes aimed to reduce the degree of highly assimilable nitrogenous proteins and parasympathetic and insulin activity: Low-glycemic, dairy and gluten-free vegetarian diet with whey protein supplements

1. Verrax J, Taper H, Calderon P. Targeting cancer cells by an oxidant-based therapy. Current Molecular Pharmacology. 2008;1:80-92.

2. del Rio B, Garcia Pedrero JM, Martinez-Campa C, Zuazua P, Lazo PS, Ramos S. Melatonin, an endogenous-specific inhibitor of estrogen receptor alpha via calmodulin. J Biol Chem. Sep 10 2004;279(37):38294-38302.

3. Kripke DF, Kline LE, Shadan FF, Dawson A, Poceta JS, Elliott JA. Melatonin effects on luteinizing hormone in postmenopausal women: a pilot clinical trial NCT00288262. BMC Womens Health. 2006;6:8.

4. Lissoni P, Barni S, Ardizzoia A, et al. A randomized study with the pineal hormone melatonin versus supportive care alone in patients with brain metastases due to solid neoplasms. Cancer 1994;73:699-701.

+Follow Up Assessment: 11/09Laboratory Chemistries

Chemistry

4/09 11/09 Comment

LDH 300 194 Reduction in chronic metabolic strain

CPK 137 90 Reduction in acute metabolic strain

CEA 0.7 <0.5 Cell adhesion molecule

CA 15-3 34 23 Associated with gonadotropic activity and thyroid’s role in hyperplasia and inflammation1,2

CA 19-9 40 34 Associated with abdominal cancers; repre-sents metabolic role of thyro-somatotropic activity

+Follow Up Assessment: 11/09Laboratory Chemistries

Chemistry 4/09

11/09

Comment

Osteocalcin 17.8

42 Serum levels are inversely related cellular metabolic activity as inducers of anabolism, as it stimulates insulin release1

BUN/Cr 29 15 Elevated BUN/Cr ratio can be associated with a hyper-catabolic state

Na 155 138

ALT 96 38

Hg 9.5 10.7 Improvement in anemia1. Atkinson SA. Vitamin D status and bone biomarkers in childhood cancer. Pediatr Blood Cancer. Feb 2008;50(2 Suppl):479-482; discussion 486.

+Follow up assessment: Biology of Functions: APOPTOSIS INDEX: Global rate of apoptosis relative to the rate of dysfunctional apoptosis during adaptation (nl 0.3-0.7)

04/27/05 11/01/05

index d'apoptose (0,3 à 0,7)

0.154674950927995 0.856911637700045

0.05

0.15

0.25

0.35

0.45

0.55

0.65

0.75

0.85

+Follow up assessment: BoFDNA FRACTURE: Degree of nuclear fragility and its risk of rupture, and by extension, of transcription errors (nl: 0.5-1.5)

04/27/05 11/01/05

index de fracture adn (0,5 à 1,5)

10.2663703584957 5.55438564714182

1.00

3.00

5.00

7.00

9.00

11.00

+Follow up assessment: BoF: Carcinogenesis index: Rate of dysplastic activity (nl: 1-3)

04/27/05

11/01/05

index de carcinogenèse (1 à 3) 240.329127240822

42.871212030001

31.62

316.23

index de carcinogenèse (1 à 3)

+Follow up assessment: BoF: Cancer index: : The relative degree of endocrino-metabolic factors which are propitious to cancerous activity (nl: 6-10)

04/27/05

11/01/05

index de cancérose (6 à 10) 1.12970951901932

0.0011378759564697

0.00

0.03

0.32

3.16

index de cancérose (6 à 10)

+Follow up assessment: BoF: Expansivity no. 2: Rate of anarchic cellular development (Pink square) (nl: 1-4)

04/27/05

11/01/05

index d'expansivité (0,06 à 2) 3.57860871097506

1.18841240349075

index d'expansivité bis (1 à 4) 6.46517095366995

1.16698146693865

index d'expansivité global (0,01 à 3,2) 7.62210210496463

4.62364016066547

0.32

3.16

+Follow up assessment: BoF: Active Carcinogenesis: Current functional state of cancer activity after accounting for cell death by apoptosis or necrosis (nl 0.01-9.6)

04/27/05

11/01/05

index de carcinogenèse active (0,01 à 9,6) 1831.81314662658

198.221057678317

index de carcinogenèse active comparée (0,01 à 4,8)

42.6350502835939

13.9188612616288

31.62

316.23

3162.28

+Follow up assessment: BoF: Estrogen index: Endocrino-metabolic activity of estrogens (nl, females: 0.2-0.4)

04/27/05 11/01/05

index oestrogénique (0,20 à 0,40 F) (0,15 à 0,25 H)

0.360346441947565 0.196047619047619

0.03

0.08

0.13

0.18

0.23

0.28

0.33

0.38

+Follow up assessment: BoF: Total Androgens (Blue diamond): total androgen activity (nl, females: 0.2-0.25)

04/27/05 11/01/05

taux d'androgènes totaux (0,2 à O,25 F) (0,2 à O,3 H)

0.443243041268836 0.261078048780488

taux d'androgènes cortico surrénaliens (0,05 à 0,09)

0.0835493520267806 0.0412652274479568

taux d'androgènes génitaux (0,12 à 0,17 F) (0,18 à 0,22 H)

0.359693689242056 0.219812821332531

0.03

0.08

0.13

0.18

0.23

0.28

0.33

0.38

0.43

0.48

+Follow up assessment: BoF: (Intracellular) Growth Index (nl 2-6)

04/27/05 11/01/05

index de croissance (2 à 6) 16.5342750133761 9.04311247165532

1.00

3.00

5.00

7.00

9.00

11.00

13.00

15.00

17.00

+Follow up assessment: BoF: Membrane Expansion (Blue) (Nl: 0.08-0.16)Structural Expansion (Pink) (nl 0.04-0.08)

04/27/05

11/01/05

taux d'expansion membranaire (0,08 à 0,16) 0.241658424628551

0.0715079601411947

taux d'expansion structurale (0,04 à 0,08) 0.0373785049707578

0.0612760032331807

0.03

0.32

+Follow up assessment: BoF: Proinflammatory (Blue): endogenous potential for inflammation (nl 0.1-0.4)Inflammation index (Pink): Current functional state of inflammation (nl 0.3-2.5)

04/27/05 11/01/05

index proinflamma-toire (0,1 à 0,4)

0.443178220955999 0.221593345339165

index d'inflammation (0,3 à 2,5)

1.34523412405595 0.0664666547697341

index d'inflammation comparée (0,2 à 2,5)

2.69046824811191 0

3.16

+Conclusions

The endobiogenic concept is an approach to integrative physiology based on the management of the organism by the endocrine system

It is a whole model system, integrative in its approach to understanding the functioning of the individual parts and their relationship to the whole

Cancer is a multifactor disorder of disregulated cell growth

The endobiogenic system is well suited to analyze the causes of cancer and its possible treatments because of its ability to simultaneously assess multiple factors that influence cell growth

+Conclusions (cont.)

The biology of functions is biological modeling software that is able to assess the quantitative, qualitative and functional activity of the organism

The biology of functions is able to provide a rational basis of treatment

It provides for longitudinal assessment of the progression of a patient’s tumor as well as their response to treatment

+Contact

For research in North and Central America, Middle East: Kamyar M. Hedayat, MD, International Society of

Endobiogenic Medicine and Experimental Physiology Email: acquamarine@mac.com Phone: 1-318-525-6311

For research in Europe and North Africa: Jean Claude Lapraz, MD, President, International Society of

Endobiogenic Medicine and Experimental Physiology Email: sfpa@club-internet.fr Phone: 011 33 6 07 71 94 00