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Science 

Summary

The AngioGenex Vision

"Seminal" is how tumor angiogenesis pioneer, the late Dr. Judah Folkman of Harvard Medical School described the AngioGenex platform technology: "The concept that there is a steady traffic of precursor endothelial cells from bone marrow into the tumor bed is a very novel, important finding," he said. The results, he went on, could open the door for a new class of antiangiogenic drugs that may help combat tumor growth." - ScienceNow, November 2001. Since he said so, Dr, Robert Benezra at Memorial Sloan Kettering, and AngioGenex, the company based on his discovery, have been working non-stop to prove Folkman right, and have developed just that class of drugs.

Folkman’s scientific challenge has led AngioGenex to create and develop a class of novel chemical entities (NCE’s). These therapeutic small molecules are rationally designed and targeted against very aggressive cancers and age-related macular degeneration, through the interruption of a basic biological process indispensible to the progression of these diseases. After rigorous scientific peer review, we have confirmed the validity and drugability of our target by hitting that target with novel and proprietary molecules that are the product of our drug extensive rational drug design and development work, and extensive pre-clinical testing in the most challenging animal models.

The Target

Since their discovery more than twenty years ago, Dr. Robert Benezra, the Company Chief Scientific and Executive Officer and a Member at Memorial Sloan Kettering Cancer Center (MSKCC), has been pursuing the role of the “Id” genes, and the proteins they express, in stimulating intrinsic cell growth and blood vessel development to support that growth that occurs both in early fetal development, and the pathology of numerous important diseases. Subsequent experiments by Dr. Benezra with an ‘Id knock-out’ mouse proved that interfering with Id protein activity prevented the establishment and spread of tumors that normally ‘dupe’ the body into activating the Id mechanism for cancer cell proliferation and to create the new blood vessels cancer cells need to grow and spread. The importance of t he Id proteins as targets essential for neovessels and tumor cell proliferation, as well as metastasis, was confirmed in numerous in vitro and in vivo models, and shared with the academic community in esteemed peer-reviewed publications. It emerged that Id protein-supported cell proliferation and neo-vascularization is central to the pathology of many forms of cancer and macular degeneration (a disease characterized by unregulated blood vessel growth in the eye), and its inhibition has a powerful positive effect on the prevention of their progression.  Peer reviewed publications discuss the Id mechanism and potential for disease prevention.

Lead Drug Candidates AGX51/AGXA

Our novel approach has resulted in compelling pre-clinical data  supporting the further development of our small molecules AGX51 and AGXA. AGX51 is a first-in-class compound that antagonizes an interaction formerly considered undruggable and which may have utility in the management of multiple diseases including age-related macular degeneration and certain cancers...AGXA is a second generation ID-inhibitor and the Company’s lead drug candidate.

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The Science 

Overview

Cancer is a genetic disease resulting in deregulated cell growth.  Tumor suppressor genes and oncogenes inhibit or stimulate cell proliferation, respectively, and are normally in balance.  Mutations in either or both of these gene classes can lead to cancer.  Over the past 20 years, much research has focused on inhibiting the growth of tumor cells by either altering the activity of oncogenes or tumor suppressors so that normal growth properties are restored. This approach has met with limited success for several reasons. Tumor cells can acquire mutations rapidly and drugs designed to kill the tumor cell or alter protein activity are often countered with further mutations leading to drug resistance. In addition, many of the oncogenes and tumor suppressors have normal counterparts that are required for normal cell functions so that inhibiting their activity often causes serious side effects and toxicities. Finally, the mechanisms of action of some oncogenes and tumor suppressors are poorly understood limiting the development of more specific drug therapies. For these reasons, alternate approaches to the management and cure for cancer have been actively pursued.

The Anti-Angiogenic Approach

One anticancer approach that has received much attention in recent years is targeting of the blood supply of the tumor. If tumors are prevented from recruiting new blood vessels for nutrients (through a process called angiogenesis) they cannot grow beyond a very small size and cannot spread (metastasize) to other parts of the body, rendering them essentially harmless to the patient. This approach is attractive because unlike tumor cells, the cells that form blood vessels do not acquire mutations at any appreciable rate and, therefore, acquired drug resistance is unlikely. In addition, the Company believes that the growth of blood vessels around a tumor is a different process than normal angiogenesis in adults, suggesting that it is possible to develop non-toxic drug regimens for treating cancer. Normal angiogenesis occurs in adults primarily in wound healing and certain reproductive functions. Finally, the molecular steps that result in angiogenesis are becoming better understood, thereby providing new targets for anti-angiogenic drug design. Among these, the Id proteins have been demonstrated to play a key role in tumor angiogenesis and not normal vascular maintenance. The Company is pursuing strategies to inactivate either the Id genes or Id proteins to inhibit the growth and metastasis of tumors.

A short video below visualizes the Anti-Angiogeneic approach.

 

 

 

A Novel Strategy for Cancer Therapy

 The Id genes act early in fetal development to promote the growth of cells and blood vessels but are turned off prior to birth and are usually inactive in adult life. Id is reactivated in many tumor cells in the early stages of the disease and, importantly, it is also expressed in the blood vessels that infiltrate tumors. Through genetic manipulations in mice it has been shown that partial loss of Id function leads to a profound inhibition of the growth and metastasis of tumors.  This inhibition can be attributed to the failure of the animals to develop an intact vasculature (network of blood vessels) within the tumor mass as well as a tumor cell-intrinsic decrease in cell proliferation resulting in significant cancer cell death. Importantly, animals with reduced Id levels show no other obvious physiological abnormalities. Thus, the Id genes and proteins become attractive drug targets for the following reasons:

·  The Id proteins have been shown to be a key component for both tumor angiogenesis and tumor cell proliferation.

·  The Id proteins are fetal specific and are only re-expressed during tumor vascularization but not in normal adult vasculature (with the exception of wound healing and reproductive functions) making it possible to design drugs that are not expected to cause side effects.

·  Only partial reduction in Id activity causes a significant inhibition of tumor angiogenesis.

·  The mechanism of Id action is well understood, thus allowing high throughput screening and rational design of drug candidates.

·  Inactivation of Id before or after tumor formation is effective in preventing or limiting tumor growth in animal models that the Company believes is reasonably predictive of human activity.

·  Compounds of a known chemical class have been identified that bind and inhibit the Id protein in a biochemical and a cell culture screen. The Company studied their activity for the design of more potent and efficient Id protein inhibitors and has selected leads for further development, for the treatment of cancer and macular degeneration.

APPLICATIONS

 There are multiple therapeutic and prognostic/diagnostic applications of the Company's Id technology platform.

Id-Based Oncology Therapeutics.

The discovery and development of one or more anticancer drugs is the primary corporate goal of AngioGenex. There is considerable evidence to demonstrate the effects of several Id proteins (Id1, Id2, Id3 and Id4) on different aspects of cellular growth. The participation of Id proteins in advanced human malignancy has been supported by the discovery that they exert pivotal contributions to essential cellular alterations that collectively cause malignant growth. The Id proteins support the formation of blood vessels into tumors as well as cell-intrinsic tumor cell growth that results in rapid growth and metastasis. These proteins comprise a particularly compelling target for drug discovery because they are either absent or present in very low concentration in normal adult tissues. They are required only for wound healing and certain reproductive functions in adults. As a result, inhibition of Id proteins would be limited to the tumor and would not be expected to affect normal cellular functions and cause toxicity like other anti-cancer drugs that are less selective. Dr. Benezra has shown that mice that are deficient in one or more copies of the Id proteins (Id1 and/or Id3) are unable to support the growth and metastasis of tumors caused by the injection of several different types of cancer cells. Negative effects of Id deletion on preformed tumors have also been demonstrated. The evidence for the lack of growth of tumors with Id efficiency has been extended by using genetically modified mice that harbor either activated oncogenes or mutated tumor suppressor genes that are commonly found in human cancers including breast and prostate. The inhibition of tumor growth in these animals is especially important since they are the most challenging models available and, as a result, are not often used by others to identify anti-cancer drugs. These are compelling models that mimic the human course of the disease because these animals are immune competent and the tumors develop spontaneously rather than grow from tumor cells that are injected into the mouse. 

Id-Related Ocular Therapeutics  

There are other important diseases besides cancer in which the abnormal growth of blood vessels contributes to the underlying pathology. These include ARMD (age related macular degeneration) and retinopathy of prematurity (ROP), where growth of blood vessels has been implicated in the loss of vision and blindness. These are major diseases for which existing treatments are unsatisfactory. Medical experts in these diseases believe, and there is some experimental evidence to suggest, that blocking the growth of blood vessels would be therapeutic. The Company has designed and tested a number of small molecules with which it has obtained promising results in two animal models used routinely to identify drugs useful to treat these diseases. The first model involves subjecting very young mice to high oxygen concentrations (hyperoxia), a procedure that causes growth of blood vessels in the eye. This model is used routinely to screen for agents to treat ROP. The absence of Id genes and proteins prevented the growth of blood vessels into the eye in this animal model. A second mouse model that employs argon laser injury was also used to investigate the role of the Id genes and proteins in ocular angiogenesis associated with ARMD. The argon laser model is the most predictive of a beneficial action of a drug or procedure for the treatment of ARMD. As in the hyperoxia model, Id deletion resulted in a failure of growth of new blood vessels into the eye. Additional research is being conducted to confirm and extend these findings, and anti-Id molecules will be used in an attempt to reproduce these results

Relevant Articles 

"A Small-Molecule Pan-Id Antagonist Inhibits Pathologic Ocular Neovascularization" (Wojnarowicz et al, Cell Reports 2019)

"Anti-tumor effects of an Id antagonist with no acquired resistance" Wojnarowicz et al, BioRxiv 2020)

 

"Rapid Chemotherapy-Induced Acute Endothelial Progenitor Cell Mobilization: Implications for Antiangiogenic Drugs as Chemosensitizing Agents" (Shaked et al, Cancer Cell 2008)

Id1 cooperates with oncogenic Ras to induce

metastatic mammary carcinoma by subversion

of the cellular senescence response (Swarbrick, Roy, Allen, Bishop, Proceedings of The National Academy of Sciences 2008)

The ID proteins: master regulators of cancer stem cells and tumor aggressiveness (Lasorella, Benezra, Iavarone, Nature Reviews: Cancer)

 

TGF-b-Id1 Signaling Opposes Twist1
and Promotes Metastatic Colonization
via a Mesenchymal-to-Epithelial Transition ​
 (Stakic et al, Cancer Cell 2013)

 

Rapid Chemotherapy-Induced Acute Endothelial Progenitor Cell Mobilization: Implications for Antiangiogenic Drugs as Chemosensitizing Agents ​ (Shaked et al, Cancer Cell 2008)

 

Annual Reports in Medicinal Chemistry, Vol. 48 ​ (Garland, Benezra, Chaudhary, Academic Press 2013)

 

Angiogenesis impairment in Id-deficient mice cooperates with an Hsp90 inhibitor to completely suppress HER2 neu-dependent breast tumors (Candia et al, Proceedings of The National Academy of Sciences 2003)

Peptide-conjugated antisense oligonucleotides for 8 targeted inhibition of a transcriptional regulator (Henke et al, Nature Biotechnology 2007)

The Id proteins and angiogenesis  (Benezra, Rafii, Lyden, Oncogene 2001)

Therapy-Induced Acute Recruitment of Circulating Endothelial Progenitor Cells to Tumors (Shaked et al, Science Magazine 2006)

 

Id proteins at the cross-road of development and cancer  Lasorella, Uo, Iavrone, Oncogene 2001)