PLACENTAL MOLECULES UTILIZING INHALATION THERAPY OFFER A NEW APPROACH FOR LUNG CANCER THERAPEUTICS
Lung cancer is the number 1 cancer killer of American women and men. It kills more people than breast, prostate, colon, liver, and melanoma cancers combined. Lung cancer kills more women than breast and ovarian cancers combined annually. The therapeutic approach has not change appreciably for decades for this usually fatal devastating disease.
Recently the Cleveland Clinic conducted a clinical trial using chemotherapeutic agents in hospital inhalators in order to treat lung caner patients. This clinical trial failed.
Nonetheless, herein we propose clinical trials with inhalation therapy, using normal human molecules obtained from human placental tissues as therapeutic agents. Placental tissues are deemed fetal. Some of the specific placental molecules have a long research history, and some of these relate specifically to the lung’s biological tissues. One of these molecules, cellular fibronectin, already had a FDA/IRB approval clinical trial that was deemed successful.
Inhalation, or respiratory therapy is a discipline of medicine that dates back to ancient times. Recent technological advances with inhalation devices have led to innovative respiratory therapies that include treatment for lung cancers. The proposal herein projects clinical trials utilizing normal human molecules obtained microbiologically from human Placental Tissues. These lyophilized molecules can be reconstituted immediately before they can be aerosolized in inhalation devices in order to infuse them into the lungs of cancer patients.
The main types of lung cancers are: Non-Small Cell Lung Carcinoma: (NCSLC) 80.4%. Small Cell Lung Carcinoma: ( SCLC) 16.8% The diagnostic distinction is important because the treatment of each varies; NSCLC in in many instances treated with surgery, while SCLC is usually treated with chemotherapeutic agents.
The lung is a common site for metastasis from tumors in other parts of the body. Nonetheless, the site of origin identifies these cancers. Thus, a breast cancer metastases in the lung is still considered breast cancer.
The present day treatments for lung cancers depends on the cancer’s specific type, how far it have spread, and the patient’s performance status. The common treatments for many decades have continued to surgery, chemotherapy and radiation therapy. Nonetheless, with these therapies the overall 5 year survival rate is 14% in the USA. This survival rate has been essentially the same for over 3 decades.
IT’S TIME FOR A NEW THERAPEUTIC APPROACH
RESEARCH EVIDENCE SHOW THAT CELLULAR FIBRONECTIN AND EXTRACELLULAR MATRIX MOLECULES MAY BE THERAPEUTIC
These molecules are already being used therapeutically. They are produced by our own bodies normal cells. These exact molecules maintain our own human cells and organs; repair defected parts; fight infections; help cells differentiate, etc.
Aria et al. (1) found that Cellular Fibronectin is the MAJOR constituent of pulmonary extracellular matrix and exists in multiple isoforms arising from alternate splicing. EDA and EDB are the two alternately spliced segments, and their research had shown the importance of fibronectins in the differentiation of fetal lung epithelial cells. Also, the EDB segment plays a regulatory role in the differentiation on immature epithelial cells that become type II pneumocytes, the actual air sac structures.
The in vitro study of Roman (2) using immunohistochemical analysis of embryos revealed increased deposition of Fibronectin during the pseudo-glandular stage of Lung development, coinciding with the period of branching morphogenesis. This observation together with the strategic location of Fibronectin around developing airways at cleft sites strongly suggests a dominant role in airways formation. Specific blockage of the Fibronectin receptor inhibits the airway formation.
Following embryonic development, the tissue expression of Fbronectin is greatly reduced, but increases markedly following tissue injury where newly expressed Fibronectin matrices appear critical to repair. There is increased expression of Fibronectin in “adult respiratory distress syndrome” (ARDS); “bronchiolitis obliterates organizing pneumonia” (BOOP); and “idiopathic pulmonary fibrosis” (IPF). (3)
The extracellular matrix (ECM) is an important determinant of type II epithelium following several types of lung injury. Both Fibronectin and Laminin which are prominent components of the ECM along with other soluble factors likely direct the cellular transitions required for restoration of a physiologically competent alveolar surface during the repair of lung injury. (4)
After in vivo denudation of type I cells, the reepithelization, of the type II cells have been observed to reorganize on the ECM that contains Fibronectin. The blockage of the Fibronectin with monoclonal antibodies negated their functional activities. (5)
Fibronectin was evaluated in the bronchopulmonary lavage fluid in patients with interstitial lung disease. Fibronectin, a normal constituent of lung tissue and epithelial fluid of the lower reparatory tract is present in increased amounts in a significant number of individuals with with interstitial lung disease. (6)
Ironically, as early as 1978, Fibronectins were were detected in both lung tissue and placental trophoblast. (7) Cellular Fibronectin was first isolated and characterized in human placental tissues in 1984. It was compared to the well studied Plasma Fibronectin and was found to be different as to their molecular weights and carbohydrate structures. (8)
A 1997 study supported the concept that Fibronectin has specialized roles in injury and repair of epithelial bronchial tissues. Fibronectin alone was able to support survival of normal bronchial epithelial cells in growth factor-deficient medium and was able to induce intergrin clustering, focal adhesion formation, and phosphorylation of focal adhesion kinase. (9)
Fibronectins deposition into the sub-epithelial spaces of the airways in all forms of Asthma early in the progression of the disease. Deemed a remodeling implication for this disease. (10)
Patients with lung cancers have high-molecular-weight form forms and domain alterations of Fibronectins in their pleural effusions. This is prevalent in all types of lung cancers. This reflects the dynamic changes caused by lung cancer’s destructive alterations in this highly prominent protein in all lung tissues and cells. (11)
OBTAINING NORMAL HUMAN MOLECULES FROM PLACENTAS
The technologies for purifying Cellular Fibronectins and appropriate Extra Cellular Matrix Molecules have been regularlly achieved by our company Fibrogenex. Suggested for two major agendas for clinical trials: 1. Fibronectins only and 2. Extracellular Matrix Molecules which will contain Fbronectins. These molecules shall be purified, sterilized and lyophilized. They will be reconstituted immediately before being placed in the inhalators in order to infuse them into the patients. Clinicians shall determine dosages and intervals between therapeutic applications.
It’s a foregone conclusion that there is moral obligation to readdress the inadequate present day therapies for lung cancers. The suggested therapies herein may be of benefit for this dyer condition. The references presented in this paper show that the conceptual proposals are supported by research. Further, there are posts on this website that show a possibility that cancer tissues may be re-differentiate into a more normal tissues given the appropriate induction protocols. From the scientific viewing of the historical research papers herein, dating back to 1978, the intention of restoring the aberrant molecules with normal molecules seems self evident.
The use of inhalation therapy is not new. Clinicians at the prestigious Cleveland Clinic recently made use of this technology in order to infuse chemotherapeutic agents for lung cancer. Those toxic agents did not work. However, the suggestive concepts herein would infuse normal human molecules that our bodies will recognize as self, because these molecules are self.
1. Aria H, et.al. Loss of EDA+fibronectin isoforms is associated with differentiation of alveolar epithelial calls in human fetal lung. Am J Pathol 1997 Aug; 151(2): 403-12
2. Roman J. Fibronectin and fibronectin receptors in lung development. xEp Lung Res. 1997 Mar-Apr; 23(2): 147-59
3. Limper AH and Roman J. Fibronectin. Versatile matrix protein with roles in thoracic development repair and infection. Chest 1992 Jun; 101(6): 1663-73
4. Rannels DE and Rannels SR. Influence of the extracellular matrix on type 2 cell-differentiation. Chest. 1989 Jul; 96(1) 165-73
5. Clark RA et al. Fibronectin mediates adherence of rat type II epithelial cells via the fibroblastic cell-attachment domain. J clin Invest. 1986 Jun; 77(6) 1831-40
6. Rennard SI and Crystal RG. Fibronectin in bronchopulmonary lavage fluid. Elevation in patients with interstitial lung disease. J Clin Invest. 1982 Jan; 69(1) 113-22
7. Bray BA. Cold-insoluble globulin (fibronectin) in connective tissue of adult human lung and in trophoblast basement membrane. J Clin Invest. 1978 Oct; 62(4) 745-22
8. Isomer M et al. Isolation and characterization of human placenta fibronectin. J Biochem. 1984 Jul; 96(1): 163-9
9. Aoshiba K et al. Fibronectin supports bronchial epithelial cell adhesion and survival in the absence of growth factors. A J Physiol. 197 Sep; 273(3 Pt 1);L684-93
10. Hocking DC. Fibronectin matrix deposition and cell contractility; implications for airway remodeling in asthma. Chest 2002 Dec; 122(6 Suppl): 275S-278S
11. Puppet M et al. Presence of high-molecule-weight forms and domain alterations of fibronectin in pleural effusion of patients with lung cancer. Clin Biochem. 2009 May; 42(7-8):654-61