Trial Information

An Open Phase II Clinical Trial of Fermented Wheat Germ Extract in Combination With Hormone Therapy for the Treatment of Hormone-Refractory Prostate Cancer Patients

Background and Significance

1. The challenge:

Prostate cancer is a major worldwide health problem and is the most frequently
diagnosed malignancy in men today. In the United States prostate cancer is the most
common malignancy found in men accounting for more than 29% of all diagnosed cancer and
approximately 13% of all cancer deaths. Nearly one in six men will be diagnosed with
the disease at some time in their lives. In 2003 alone, an estimated 221,000 men in the
United States were diagnosed with prostate cancer. In 1999, 37,000 deaths were
attributed to prostate cancer in the United States, and in 2003 more than 28,000 died
of the disease. Hormone-refractory prostate cancer (HRPC) is one of the most aggressive
cancers. It is the second ranking cause of cancer-related deaths. Patients with
localized disease have the option of radiation therapy or radical prostatectomy as
definitive treatment modalities for curing the disease. However the cancer recurs in
its metastatic form in 20-30% of these patients. In addition, approximately 10 % of
patients diagnosed with the disease already have distant metastases, making localized
therapy irrelevant. The primary treatment for the advanced state of prostate cancer is
androgen deprivation therapy, to inhibit the testosterone production that facilitates
prostate tumor growth. Androgen deprivation therapy is administered either by surgical
castration or by medications that block testosterone production. While this treatment
is effective in 85%-95% of patients, the response time lasts approximately for 12 -24
months, after which the cancer progresses to its androgen-insensitive stage. The
androgen independent prostate cancer cells progress to metastatic disease. Limited
treatment options exist for the hormone refractory prostate cancer (HRPC) patient, and
median survival time rarely exceeds one year.

Once androgen independence has occurred, conventional chemotherapy for the treatment of
metastatic cancer has shown limited activity in patients in addition to causing toxic
side effects. While new chemotherapeutic regimens and hormonal agents are being tested,
the survival and quality of life of these HRPC patients remains low.

2. The innovation:

We propose to treat progressing HRPC patients with a novel combination of 1st line of
hormone therapy (GnRH analogues) with the non-toxic dietary supplement fermented wheat germ
nutriment (FWGE). This suggestion is based on preclinical data showing activity of the
regimen in prostate cancer cell lines and in animal models. Furthermore, there are previous
reports regarding other diseases such as colon cancer, where the addition of a new treatment
to a therapy which had previously failed, improved patient survival, quality of life and the
clinical parameters.

The characteristics of Fermented wheat germ extract (FWGE) Fermented wheat germ extract with
a standardized complex mixture of molecules is termed FWGE. The product is manufactured
under GMP conditions, and is available as a water-soluble granulate, which administered
orally.

The compound is approved as a medical food for cancer patients. It has been recently
classified in the US as GRAS (Generally Recognized as Safe), and is used for complementing
the standard anticancer treatments.

The molecular targets of FWGE include poly (ADP-ribose) polymerase (PARP), major
histocompatibility complex (MHC) class I, transketolase (TK), ribonucleotide reductase (RNR)
and, intracellular adhesion molecule (ICAM) 1. By activating the caspase-3 downstream
proteases, FWGE treatment results in cleavage of PARP thus, preventing DNA repair in cancer
cells.

FWGE treatment decreases major histocompatibility complex class I (MHC-I) in cancer cells.
MHC-I down regulation in cancer cells leads to an increased natural killer (NK) cells'
activity. NK cells are considered as the first line of anticancer immune defense.

TK is the key enzyme of the reductive pentose cycle. In cancer cells this cycle is
responsible for supplying these cells' increased need for ribose molecules necessary for
synthesis the sugar chains of the nucleic acids. RNR enzymes, which are strongly inhibited
by FWGE, catalyze the synthesis of the DNA components.

It has been known that a tumor can not grow bigger than 2 mm in diameter except if it is
able to synthesize its own blood vessels (angiogenesis process). The blood vessels in tumors
lack the protein ICAM-1, which is responsible for facilitating the transfer of anticancer
immune cells (e. g. macrophages) via the vessels' walls into the tumor. FWGE treatment
increases the synthesis of ICAM-1.

In addition, FWGE has a wide therapeutic window: In order to observe any toxicity (effects
on normal cells), more than 50 times higher dosage of FWGE than the recommended one for
therapy is needed. This very positive toxicity profile gives a wide therapeutic window for
the applicability of this product.

Recently, it has also been shown that FWGE is a strong but, non-selective inhibitor of the
cyclooxygenases 1 and 2 thus, this preparation has an anti-inflammatory activity.

The preparation has also been shown to induce apoptosis in gastric carcinoma cells.

Advantages of FWGE:

- The FWGE preparation is non-toxic and safe. This serves as a major consideration in its
selection for the treatment of advanced cancer patients who suffer from low performance
status and consequently have a poor quality of life.

- FWGE is orally administrated.

- The FWGE preparation exhibits a wide variety of mode of actions, in a wide range of
malignant tumors.

- The product is able to increase the natural immune responses, while decreasing the
systemic inflammation often present in the patients.

- It is anticipated that FWGE, by complementing therapeutic efficacy of the standard
hormonal anticancer treatments, could suppress disease progression, thus prolonging
patients' survival and improving quality of life parameters.