Executive Summary

Fore by Four: A novel anti-cancer drug-combination

 Prof. Muli Ben Sasson

Introduction: After sixty years of conventional chemotherapy, the approach directly targeting the tumor cells, reaches its limits. To date, cancer still remains one of the major causes of death in the Western world. On the other hand, we came to terms with the realization that tumor growth is determined not only by the genetic makeup of malignant cells but to a large extent by complex interactions with the surrounding healthy tissue. Of utmost importance is the ability of the tumor to recruit blood vessels from the neighboring tissue.

Angiogenesis, the process by which new blood vessels are formed, is a hallmark capability of cancer. Blood vessels are composed of endothelial cells which jointly form continuous tubes. A compelling body of evidence argues that tumor growth depends on the vasculature and, in particular, on continuing angiogenesis (1). Accordingly, an anti-angiogenic therapy (i.e. attempts to starve the tumor to death by cutting-off its blood supply) has emerged as a most promising strategy to inhibit tumor growth and spread.

Fore by Four (4X4) technology: At present, the field already passed the proof of principle stage. The current challenge is to generate an anti-angiogenic therapy that will be successful enough to become a powerful anti-cancer agent in the clinic. To that end, 4X4 explored a broad spectrum of potential anti-angiogenic agents, in an integrative way. Our working hypothesis was that since angiogenesis is a multi-facet process that involved multiple steps (e.g. endothelial cell proliferation, migration, tube-formation etc.), an anti-angiogenic drug -combination is a preferred choice and can be constructed on a rational basis. In other words, we recruited to our side a vast volume of knowledge, already exists in the literature, and used it in an innovative way. Unlike the common trend in the field, typified by a search for new, expensive, recombinant proteins or antibodies, 4X4 efforts concentrated on orally bioavailable, low molecular weight, drugs that were already approved for use in the clinic. As a starting point, we chose the achievements obtained by “metronomic dosing” Metronomic dosing accounts for the ability to target the proliferating endothelial compartment of the tumor bed by an increase of the frequency and a decrease in the dosing of conventional chemotherapy (for a review see 2). This way, a known chemotherapeutic agent like cyclophosphamide (CTX) was converted into a potent anti-angiogenic drug.

The 4X4 solution: Because of the inherent limitations of conventional chemotherapy, metronomic dosing must be complemented by other drugs in order to create an effective and safe anti-angiogenic therapy. To that end we systematically searched for compounds that might synergize with CTX by virtue of their independent mechanism of action on the angiogenic process.

Through a concerted effort of detailed screening we were able to identify three non-oncologic agents (“ABC”) that synergize with CTX in their anti-angiogenic and anti-tumor activity. As stated above, all four drugs, including CTX, are orally bioavailable and are approved for a use in the clinic. Despite FDA approval of each compound by itself, the chemistry an bioavailability of the components requires that they be formulate together into a unique composition.   This requirement will prevent off-label separate prescriptions for each drug.  The unique  composition is covered by the patent application and will be the focus of drug development. It is important to stress that the anti-tumor effect of each individual component (A, B or C), by itself, is very minor while only the full combination provides the robust synergy, as demonstrated reproducibly by our own work. 

4X4 scientific strategy and extensive efforts, resulted in the development of a powerful, novel, drug-combination that yielded a dramatic anti-cancer effect when tested in-vivo in one of the most malignant breast cancer tumor model in mice. The anti-angiogenic mechanism of action of this drug-combination was also demonstrated in an in-vivo model of wound healing (4). Moreover, the addition of the ABC combination enables a further reduction (by 50%) of the CTX dose, as compared with that required according to the original protocol of Browder et al (3).

Market Size: Anti-angiogenic therapy appllies to all solid tumors (lung, breast, prostate, colon cancer etc.). Thus, its market size is at the range of 2 to 10 Billion dollars. For example, the proprietary drug Herceptin which target only 30% of breast cancer patients, (i.e. about 3% of all cancer patients), has currently a market size of about $600 million dollars.

References:

1. Hanahan D, Folkman J.

Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell. 1996, 86:353-64.

2. Gately S, Kerbel R.

Antiangiogenic scheduling of lower dose cancer chemotherapy. Cancer J. 2001, 7:427-36.

3. Browder T, Butterfield CE, Kraling BM, Shi B, Marshall B, O'Reilly MS, Folkman J.

Antiangiogenic scheduling of chemotherapy improves efficacy against experimental drug-resistant cancer. Cancer Res. 2000, 60:1878-86.

4. Abramovitch R, Marikovsky M, Meir G, Neeman M.

Stimulation of tumour growth by wound-derived growth factors.
Br J Cancer. 1999, 79:1392-8.

Current status: Proof of concept in mice and rats showed excellent results. 4X4 is now in the process of raising complimentary financing in order to (1) move forward with FDA-compliant pre-clinicals, (2) strengthen its IP position, and (3) based on pre-clinical data, 4X4 is aiming at moving straight into 'compassionate' (fast track) and Phase I/II human clinical trials, since these are known and approved agents that have been reformulated by the company in a sophisticated manner.

Objectives and time table: Winding up the preclinical study, treatment of cancer patients on an individual basis (around 5 compessionate requests) and IND filing, by the end of 2003. Complete Phase I/II clinical trial by the end of 2005 (24-36 cancer patients). In parallel, substantiation of the anti-angiogenic mechanism of action of the drug-combination and identification of new targets for this anti-angiogenic therapy (e.g. ophthalmology).

IP status: A world-wide patent application (PCT) that broadly covers the scope of the invention, was filed December 31^st, 2002. The rights for the patent are jointly held by Hebrew University (75%) and Harvard-Affiliated Children’s Hospital (25%).

4X4 business model: Establishing  a company that will complete the drug development, perform a pre-clinical study followed by a phase I/II clinical trial and at that stage will seek collaboration with a major Pharma company. 4X4 will outsource R&D to the Hebrew University and pre-clinical and clinical studies to CROs.

4X4 Team: This enterprise was initiated by Prof. Shmuel (Muli) Ben-Sasson of the Dept. of Experimental Medicine & Cancer Research, The Hebrew University-Hadassah Medical School, Jerusalem, and Mr. Yigal Stav.. Prof. Ben-Sasson also holds a position of a Visiting Professor at the Harvard Medical School, where he works in close collaboration with the world leader in the field of tumor angiogenesis, Prof. Judah Folkman, Dept. Surgical Research, Children’s Hospital, Boston.

Yigal Stav has 20 years of track record as one of the most successful CEOs in Israel. Yigal holds M.Sc. degree in Physics, a B.Sc. degree in Mathematics and Physics and an  MBA degree.

This team is working together with the academic institutions on the establishment of 4X4.

Appendix

Below is an illustration of the efficacy of 4X4 drug-combination:

The figure illustrates the effect of metronomic dosing of either CTX or ABC by themselves vs. the full combination, on the rate of tumor growth. The synergistic effect is clearly evident and the benefit of the drug-combination was reflected also in the survival rate. The tumor used in this study is EMT6/CTX; a highly malignant mouse breast cancer which is also drug-resistant. Each group contains 7 mice.

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