Targeting ovarian cancer STEM cells

Dr. Weeks’ Comment: Success targeting cancer STEM cells – hope for those with ovarian cancer.

 

“…Growing evidence suggests that chemo-resistance is due to the presence in the tumor of a population of cancer cells with stem cell-like properties that are inherently drug-resistant, surviving radiotherapy and chemotherapy to produce a recurrent cancer re-populated with a new generation of chemo-resistant cancer cells…There is an urgent need to develop treatments that will kill this population of stem cell-like cancer cells before they have a chance to establish a high degree of chemo-resistance…”

Cantrixil Highly Successful in Preventing Growth of Chemo-Resistant Ovarian Cancer— Animal model highly representative of late-stage ovarian cancer in women

PHILADEPHIA, April 20, 2015 /PRNewswire/ — US-Australian drug discovery company, Novogen Ltd, (ASX:NRT; NASDAQ: NVGN), its subsidiary, CanTx, Inc, and Yale University today disclosed key pre-clinical data on experimental anti-cancer drug, Cantrixil, justifying the optimism in the ability of this drug candidate to significantly improve the survival outlook for patients with ovarian cancer. The data was presented by Professor Gil Mor of Yale Medical School to the American Association for Cancer Research (AACR) Annual Meeting.

Development of chemo-resistance is a major hurdle in the management of patients with ovarian cancer and this phenomenon is responsible for the high mortality associated with this disease. Growing evidence suggests that chemo-resistance is due to the presence in the tumor of a population of cancer cells with stem cell-like properties that are inherently drug-resistant, surviving radiotherapy and chemotherapy to produce a recurrent cancer re-populated with a new generation of chemo-resistant cancer cells.

There is an urgent need to develop treatments that will kill this population of stem cell-like cancer cells before they have a chance to establish a high degree of chemo-resistance. That is the rationale behind the development of Cantrixil, and the current data suggests that Cantrixil has the potential to be such a breakthrough treatment.

Researchers at the Yale Medical School have established clinically relevant in vitro and in vivo models of chemo-resistant ovarian cancer, providing a tool that drug developers increasingly are accessing to screen prospective drugs against. This is a highly stringent screen that Yale believes provides a rapid go/no-go decision point for lead drug-candidates. To date, no drug candidate has provided a meaningful or durable anti-cancer effect in this model. In this highly aggressive model, intra-peritoneal Cantrixil treatment effectively prevented tumor recurrence by 95%.

In vitro studies have been reported previously. TRXE-002 initially was identified as having potent activity against epithelial ovarian cancer (EOC) stem cells, inducing cell death (apoptosis) in a library of patient-derived EOC stem cells (IC50 of 130 – 250 nM).

To replicate recurrent ovarian cancer in vivo, Yale researchers inject human ovarian cancer stem cells directly into the peritoneal cavity of mice where they develop into a highly aggressive cancer that spreads throughout the abdominal cavity. The appearance and behavior of the cancer mirrors human ovarian cancer primary disease. Once established, the mouse then is treated with the chemotherapy drug, paclitaxel, the standard first-line treatment for ovarian cancer. Following an initial partial response, the tumor quickly regains rapid growth despite ongoing paclitaxel therapy. This produces a late-stage cancer condition (secondary or recurrent disease) that replicates the situation that Cantrixil will encounter initially in the clinic.

In the model of primary disease, Cantrixil administered intraperitoneally as a monotherapy inhibited tumor growth in a dose-dependent manner, significantly reducing terminal tumor burden by >90% (dosage 100 mg/kg; p<0.01) over 17-days of treatment. The treatment was well tolerated with no evidence of bone marrow toxicity or local abdominal toxicity.

More importantly, Cantrixil performed equally well in the far more stringent model of recurrent disease. In this model, following an initial 12-day treatment period with paclitaxel, tumors failed to recur (<95% terminal tumor burden) in those animals switched to daily treatment with intra-peritoneal Cantrixil, compared to animals that remained on treatment with paclitaxel.

Lead Investigator, Gil Mor MD PhD, said, “This animal data shows that it is possible with a drug that targets the chemo-resistant ovarian cancer stem cells to prevent recurrence. Taken together, the data from both the primary and recurrent disease models demonstrate that not only is Cantrixil effective as a first-line monotherapy in a clinically relevant model of ovarian cancer, but more importantly it also prevents tumor recurrence, again in a highly relevant model of drug-resistant and recurrent ovarian cancer,” Mor added.

David Brown PhD, Novogen Group Chief Scientific Officer, said, “Gil Mor’s team have shown that cell death from TRXE-002 is associated with the activation of the pro-death JNK pathway, concurrent with down-regulation of the MAPK pro-survival pathway through prevention of p-ERK signaling. As a molecular biologist, this is a particularly exciting discovery because this novel dual effect on cell-death and cell-survival pathways is believed to explain why TRXE-002 is such an efficient killer of both ovarian cancer cells and the highly chemo-resistant ovarian cancer stem cells, and opens up the opportunity for an entirely new class of chemotherapy.”

Graham Kelly, Novogen Group Chief Executive Officer, said, “It is easy to downplay the importance of pre-clinical data. But the significance of this data needs to be seen in the perspective of the high failure rate of anti-cancer drugs that enter the clinic. For every 50 experimental anti-cancer drugs that enter the clinic, only 1 or 2 ever make it to market. There are a multitude of reasons for this appallingly high attrition rate, but one of the main ones is the lack of relevance of the animal model that was used to justify bringing it into patients in the first place.

“The animal models developed by Yale bring an entirely new level of stringency to the quest for finding an effective treatment for both primary and recurrent ovarian cancer. The performance of Cantrixil in a model that arguably is the most representative of human ovarian cancer yet developed gives us reason to be confident about the potential of this agent as a new form of chemotherapy for this significant unmet clinical need.”

About Cantrixil

Cantrixil is a cyclodextrin envelope containing the active ingredient, TRXE-002. The construct has been designed as an intra-cavity chemotherapy to be injected directly into the peritoneal and pleural cavities without causing local irritation or toxicity. Its purpose is to achieve high drug levels in the environment in which the cancer is spreading through the migration of the cancer stem cells are spreading. The ultimate primary indication of Cantrixil to be sought is first-line therapy of early-stage cancers of the abdominal cavity (e.g. ovarian, uterine, colo-rectal and gastric carcinomas). Cantrixil will enter the clinic in later-stage cancers where the abdominal carcinomatosis has resulted in the terminal condition of malignant ascites.

Cantrixil is owned by CanTx, Inc.

About TRXE-002

TRXE-002 is a small molecule cytotoxic belonging to a family of compounds whose anti-cancer function is based on various biological effects including inhibition of trans-membrane electron-transfer mechanisms. TRXE-002 is pan anti-cancer acting, resulting in caspase-dependent apoptosis of both stem cell-like cancer cells and their daughter cancer cells. The compound has a high therapeutic index with little cytotoxic effect on non-tumor cells.

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