Dietary Indole Analogs Inhibit Breast Cancer Cell Invasion

Institution: SRI International
Investigator(s): Ling Jong, Ph.D. -
Award Cycle: 2003 (Cycle IX) Grant #: 9WB-0110 Award: $381,491
Award Type: STEP Award
Research Priorities
Detection, Prognosis and Treatment>Innovative Treatment Modalities: search for a cure



Initial Award Abstract (2003)
Breast cancer recurrence is a potential threat for anyone who has been diagnosed with the disease. Up to half of patients with recurrent breast cancer will eventually have metastatic disease, which is often fatal. Despite considerable effort to improve the survival rates of breast cancer patients, the curability and survival are far from satisfactory. It is important to emphasize that breast cancer only is life threatening when it becomes invasive, at which point it carries the potential for spreading and metastasis. It is invasion that leads to metastasis and turns cancer into an incurable disease. Therefore, preventing cancer invasion is a crucial step in the achievement of cancer cure.

Cancer recurrence is very likely to result from those undetectable residual cancer cells left after breast cancer surgery. Therefore, if we can develop a safe maintenance therapy to indefinitely suppress any possible residual cancer cells left in patients after primary treatment of breast cancer, we can achieve the equivalent of "cure" of breast cancer. We have identified a novel class of dietary-based indole analogs that appears promising for maintenance therapy after primary treatment of breast cancer to prevent disease invasion and recurrence and therefore increase the overall survival of breast cancer patients. Our dietary indole analogs have proven activities against cancer growth and invasion and have a great likelihood of being safe for long-term disease control. The goal of this proposed STEP award will be to evaluate these promising candidates for maintenance therapy.

Convenience and cost are the most important considerations in the development of long-term maintenance therapeutics. Nevertheless, the treatment must also be safe. Consideration must also be given to patients in older age groups, since they are less likely to tolerate aggressive chemotherapy because of health limitations. Therefore, drugs with well-tolerated or no clinical toxicities and good oral activity suitable for chronic administration will be immensely valuable for breast cancer maintenance therapy.

In this STEP award we will perform preclinical development of our most promising novel indole analog as a long-term adjuvant therapeutic to prevent cancer recurrence and metastatic spread. We will study our most promising drug candidate for its mechanism of inhibition of cancer metastases, including the cancer cells' survival pathway and their ability to regulate cancer invasion suppressor molecules in cell cultures. Since tumors require a blood supply to survive, grow, and metastasize, inhibition of new blood vessel growth (angiogenesis) has become an exciting target for novel anticancer therapies. Thus, we will also evaluate our analogís potential for inhibition of angiogenesis.

Animal studies are essential to determine the effectiveness and side effects of the compound as a potential drug for humans. This preclinical study will include evaluation of the efficacy of our most promising analog by tumor histological and pharmacodynamic studies, as well as toxicity studies. Our novel indole analogs are expected to meet all these criteria. They will be orally administered, safe for long-term use, and effective against breast cancer invasion and metastatic spread. Their expected lack of toxic effects will be important for maintaining a patientís quality of life without debilitation.


Final Report (2007)
Introduction. Breast cancer is the most common invasive malignancy, and it is the invasive and metastatic of breast tumors that confound treatment. Novel agents or treatments are urgently needed to improve the outcome for the large number of patients who relapse after receiving the currently available breast cancer therapies, since the existing therapies are no longer effective in these patients.

We have discovered and developed a potent, orally active anticancer agent, SR13668, based on the naturally occurring anticancer agent indole-3-carbinol from cruciferous vegetables, that significantly inhibits estrogen-dependent and -independent breast tumors in animal models and does not cause unwanted side effects. Biological studies show that SR13668 can inhibit phospho-Akt (pAkt) in breast cancer cells both in cell cultures and in mouse models. Inhibition of pAkt is likely to lead to superior cancer control, because pAkt positive patients are more prone to relapse with distance metastasis.

Progress toward specific aims. At the end of the project, we were very pleased to report that we successfully completed and exceeded all the specific aims we set in this research grant. The goal in the last year was to conduct a repeat-dose oral toxicity study for SR13668. However, we decided to add an extra but extremely important Specific Aim (pharmacokinetics study of SR13668) prior to our planned oral toxicity studies, since understanding the pharmacokinetic profile of SR13668 will help us to better interpret the results from our oral toxicity data. Our PK studies show that SR13668 is orally active and distributes extensively into tissues and persists in tissue for substantial time. We next conducted the safety study of SR13668 as planned. Our results look very promising. The female Sprague-Dawley rats were administered a daily oral dose of SR13668 at dose levels of 25, 75, 200, and 600 mg/kg, which are 3-60 times higher than the effective anti-tumor dose of SR13668. No sign of drug-related mortality and organ toxicity was noted. Based on the lack of treatment-related adverse effects in the toxicity study, SR13668 looks promising for further clinical development as a novel agent for breast cancer treatment as well as long-term adjuvant prevention.

Future directions. Since the safety studies of SR13668 showed great promising, the National Cancer Institute has agreed to support all the preclinical studies. We hope that SR13668 can soon enter clinical development to benefit breast cancer patients.

Impact. Distant metastasis is responsible for the death of nearly 45,000 women per year in the United States alone. Our drug candidate, SR13668, potently inhibits the cell-survival-promoting oncoprotein Akt, and is effective against breast cancer growth and invasion. Successful development of SR13668 for clinical use may provide a new and greatly improved weapon to combat breast cancer, and bring us one step closer to a cure.


Symposium Abstract (2005)
Although breast cancer research has developed at a rapid pace over the last decade, the curative potential of currently available therapies remains disappointing. Inhibiting breast cancer proliferation via the estrogen receptor is currently the basis of the most successful therapies, but eventual resistance to endocrine therapy has become a significant clinical problem and is the underlying cause of cancer relapse and distant metastasis. An aggressive approach to breast cancer control must seek novel weapons, supplementing conventional areas such as endocrine therapy and cytotoxic drugs with new agents that target other hallmarks of malignancy found to be critical in tumor invasion and metastasis.

The cell-survival-promoting oncoprotein Akt has attracted much attention because of its central role in regulating multiple cellular processes such as apoptosis, cell proliferation, angiogenesis, cell motility, and metastasis. Activation of Akt in breast cancer patients indicates aggressive tumor behavior, resistance to hormone-, chemo-, and radio-therapy-induced apoptosis and has a significant correlation with decreased overall survival. Furthermore, the constitutively activated oncoprotein Akt is causally involved in the malignant progression of human cancers and apparently spares normal and non-neoplastic tissues. Thus, selective inhibition of elevated Akt provides an opportunity to hinder the proliferation of malignant cells while minimizing toxicity to the host.

We have developed a novel anticancer agent, SR13668, from a naturally occurring anticancer agent indole-3-carbinol (I3C), found exclusively in cruciferous vegetables such as broccoli, cauliflower, cabbage. Extensive preliminary studies show exciting results: SR13668 (1) exhibits potent oral anti-tumor activity against both estrogen-dependent and -independent breast tumors in animal models; (2) is non-cytotoxic and non-mutagenic in Ames tests; (3) inhibits Akt activation in breast cancer cells both in vitro and in vivo; (4) is anti-angiogenic, and anti-invasive and induces apoptosis; (5) shows no adverse effects on glucose metabolism; and (6) has no undesirable metabolic or estrogenic characteristics.

A key reason for our choosing to develop a novel anticancer agent by improving upon a dietary component known to have anticancer activity was the excellent likelihood that such a drug would be safe for cancer treatment without undesirable side effects. SR13668 thus represents an exciting new approach for treatment of breast cancer and offers breast cancer patients the hope of more effective cancer control with a favorable toxicological profile. SR13668 is likely to have two potential clinical applications: (1) single agent therapy for breast cancer prevention and treatment, and (2) combination therapy with hormone or cytotoxic therapy to enhance the efficacy of existing therapies and improve the quality of life of breast cancer patients. Successful development of this novel drug candidate for clinical use may bring a new and improved weapon to combat breast cancer, and hopefully the cure of breast cancer will be one step closer.


Symposium Abstract (2007)
Breast cancer is the most common invasive malignancy, and the confounding problem in treatment of breast cancer is the invasion and metastasis of breast tumors. Novel agents or treatments are urgently needed to improve the outcome for the large number of patients who relapse after receiving the currently available breast cancer therapies, since these therapies are no longer effective after a relapse. We have discovered and developed a potent, orally active anticancer agent, SR13668, based on the naturally occurring anticancer agent indole-3-carbinol, from cruciferous vegetables. SR13668 significantly inhibits estrogen-dependent and -independent breast tumors in animal models and does not cause unwanted side effects. Biological studies show that SR13668 can inhibit phospho-Akt (pAkt) in breast cancer cells both in culture and in mouse models. Inhibition of pAkt is likely to lead to superior cancer control because pAkt-positive patents are more prone to relapse with distant metastases.

To understand the pharmacokinetic profile of SR13668 and to better interpret the toxicological results, we conducted a tissue distribution study of SR13668 prior to the planned oral toxicity studies. Our pharmacokinetic studies show that SR13668 is orally active, distributes extensively into tissues, and persists in tissue for a substantial period. In our safety study, female Sprague-Dawley rats were administered a daily oral dose of SR13668 at 600 mg/kg, which is 60 times the effective antitumor dose. No signs of drug-related mortality or organ toxicity were noted. Given the absence of treatment-related adverse effects in the toxicity study, SR13668 looks promising for further clinical development as a novel agent for breast cancer treatment and as a long-term adjuvant therapy to prevent relapse.

Distant metastasis is responsible for the death of nearly 45,000 women per year in the alone. Our drug candidate, SR13668, developed with funding from CBCRP, shows potent activity against the cell-survival-promoting oncoprotein Akt, and is effective against breast cancer growth and invasion. The National Cancer Institute plans to initiate a Phase 0 clinical study to develop an oral formulation of SR13668 for a future cancer prevention trial. Successful development of SR13668 for clinical use may provide a new and greatly improved weapon to combat breast cancer, and bring us one step closer to a cure.