Recycled or revamped therapeutics find novel anti-cancer applications

November 16, 2005

PHILADELPHIA -- A second look at compounds and drugs, some previously used to treat illness and conditions ranging from malaria to contraception, is giving new life to several abandoned therapies and new applications for existing drugs.

From drugs such as the cottonseed extract gossypol, once tested as a male contraceptive in China, to arsenic, which can be made less toxic in an organic form, new applications are being investigated for effectiveness against solid tumors of various types.

A press briefing features at the "Molecular Targets and Cancer Therapeutics" International Conference here is spotlighting a few of these compounds and drugs that are undergoing recycling as possible cancer treatments.

These include:

Thalidomide, a notorious drug once linked to birth defects that is undergoing patient testing in combination with a growth factor against prostate cancer.

A drug developed as an insecticide now helping scientists to understand the microtubule assembly process that is important for pancreatic cancer cell growth.

Gossypol, once touted as a potential male contraceptive, may find a new use -- helping certain head and neck cancers overcome their resistance to cisplatin.

An organic form of arsenic that is showing some potential as a treatment for solid tumors.

Drugs currently used around the globe to treat people infected with malaria may address a critical cell nutrition issue with proliferating cancer cells.

Phase II Trial of Granulocyte-Macrophage Colony Stimulating Factor (GM-CSF) plus Thalidomide in Patients with Hormone Naïve Prostate Cancer (HNPC) (Abstract 3230)

A combination of two drugs already in use to treat certain cancers offers a potential strategy to treat prostate cancer - without subjecting men to existing effective therapies that squelch the production of testosterone.

The novel approach involves the use of thalidomide and GM-CSF, or granulocyte-macrophage colony stimulating factor, a protein produced in humans that stimulates immune system blood cell proliferation.

"GM-CSF plus thalidomide can be used successfully with encouraging anti-tumor activity," said Robert J. Amato, D.O., director of the Genitourinary Oncology Center, The Methodist Hospital Research Institute, in Houston, Texas. "This may represent an alternative to hormonal ablation therapy."

Long-term androgen suppression therapy (more than one year) can lead to significant side effects, including bone density loss, anemia, breast enlargement, hot flashes, impaired memory, and impotence in some patients, especially among elderly men.

"Existing hormone ablation therapy is effective and palliative," said "Many patients, however, hesitate to begin hormonal therapy due to the adverse effects."

GM-CSF is a cytokine that promotes the production of antigen-presenting cells, such as dendritic cells. It has been studied for its effect on colon, myeloma, ovarian and prostate cancer, as well as other non-cancerous conditions such as Crohn's disease.

Thalidomide is a polyphenyl drug that gained notoriety for its effect on developing human fetuses during the 1950s and 1960s. At that time, it was prescribed as a sleeping aid, but was banned from use because of the birth defects it caused. Much of its deleterious effects on development in early body formation in babies were related to its function in thwarting angiogenesis - the development of new blood vessels in growing tissue, or in tumors. In addition to inhibiting angiogenesis, thalidomide contributes to enhanced immune response.

In a Phase II trial conducted by Amato and colleagues, the study included men who had either a radical prostatectomy (n = 7); radiation therapy (n = 6); or both (n = 5). The study participants, who had not previously undergone hormone ablation therapy, were treated with three doses per week of GM-CSF, and thalidomide once daily at bedtime. Doses were scaled to determine maximum tolerable levels of thalidomide. Amato and colleagues observed PSA levels in the men at six-week intervals.

"All of the men in the study had a 26 percent or greater reduction of PSA blood levels," Amato observed. "The median response was 59 percent."

Patient response to toxicity of the trial drug regimen was contained to predominantly grade 1 or 2, Amato said, manifested predominantly in transient skin rash, fatigue, peripheral neuropathy and constipation. One patient, however, developed a deep vein thrombosis and pulmonary embolism.

The Efficacy of Novel Benzoylphenylureas Analogs in vitro and in a Novel Pancreas Cancer Direct Xenograft Model, and its Relationship with Microtubule-associated Protein Tau (Abstract 3077)

Researchers from Johns Hopkins University have discovered that a form of a compound originally developed as an insecticide significantly reduces the growth of a specific class of pancreatic tumors.

According to their results, analogs for the would-be insecticide benzoylphenylurea (BPU), and analogs with improved activity under clinical development at Johns Hopkins, inhibited growth by approximately 40 percent among human pancreatic tumor grafts in mouse models.

"Two derivatives of BPU showed the highest level of growth arrest on human pancreatic cell lines," said Antonio Jimeno, M.D., Ph.D., a clinical researcher in the Gastrointestinal Cancer Program at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins.

"BPU-410 and BPU-430 inhibited cell viability as well as the ability of cells to establish clonal colonies in vitro."

When the compounds were tested for their ability to thwart pancreatic tumor cell growth in animal models, the efficacy of the compound was related to the target cell's ability to express low levels of a protein called MAPT (microtubule-associated protein tau). While pancreatic cell expression of MAPT was not dependent on treatment with the BPU analogs, those cells from pancreatic tumors that had low levels of both MAPT RNA message and protein were most susceptible to the growth-inhibiting effects of the novel BPU derivatives.

Both BPU-410 and BPU-430 were effective in nanomolar concentrations, which are considered very low in pharmaceutical dose ranges for therapeutics.

For the drugs to be beneficial in clinical applications of human pancreatic cancer patients, MAPT expression levels will have to be an integral component of the proteomic profile of a sub-group of all human pancreatic cancer patients.

"As we accrue the ability to identify individual pancreatic cancer patients who are likely to respond to treatment with BPU analogs or other microtubule-targeting drugs, we also may be gaining an additional therapeutic drug to contribute to the control of this otherwise unrestrained type of cancer, and we would be taking a step forward in the individualization of therapy" Jimeno said.

Overcoming Cisplatin Resistance in Head and Neck Cancer by Targeting Bcl-xL Using a Novel Small Molecule (Abstract 3256)

In nature, cotton seed produces two forms of gossypol - a 'left handed' and a 'right handed' form of the molecule.

Cancer researchers from the University of Michigan have discovered that gossypol made as a left handed isomer - and only the left handed form - inhibits head and neck squamous cell carcinoma (HNSCC) cell growth that has become resistant to cisplatin, a front line chemotherapeutic drug. That active anti-tumor cottonseed polyphenol is designated (-)-gossypol.

"(-)-Gossypol restores the activity of cisplatin in HNSCC cells that have become resistant to chemotherapy," said Joshua Bauer, a graduate student in pharmacology at the University of Michigan Comprehensive Cancer Center.

"Outright resistance to cisplatin in HNSCC patients develops in about a third of head and neck tumors," Bauer said. HNSCC cells that become cisplatin-resistant often overexpress copious amounts of a molecule called Bcl-xL, which in some capacity interferes with the ability of cisplatin to bind to tumor cell DNA, thwart repair mechanism activity, and induce cell death. Bcl-xL enables HNSCC cells to survive when they should die.

Bauer and his colleagues postulate that (-)-gossypol binds to Bcl-xL at a site that inactivates the cancer promoting protein.

Furthermore, "the timing and sequence of treatment with the chemotherapeutic drug combination of (-)-gossypol and cisplatin is critical in reaching maximum synergistic response in HNSCC tumors that are cisplatin resistant," said Bauer.

In HNSCC cell lines resistant to cisplatin, treatment first with cisplatin, and then with (-)-gossypol resulted in a synergistic cell death rate of approximately 70 percent. Treatment with cisplatin alone resulted in only 5-7 percent cell death; treatment with (-)-gossypol yielded 30-40 percent cell death. A similar pattern of response to the drug combination was also observed in cell lines engineered to produce high levels of Bcl-xL.

Cells that were not resistant to cisplatin were additively responsive to the chemo combination. While cisplatin alone caused 70 percent cell death among non-resistant HNSCC cells, and (-)-gossypol induced 25 percent cell death when applied alone, the combination administered sequentially resulted in approximately 90 percent cell death regardless of which drug was introduced first.

Head and neck cancer is the sixth most common cancer world wide and in the United States there are approximately 40,000 new cases diagnosed annually and 10,000 people die annually of this disease. Head and neck cancer is endemic in India, so worldwide it is a major cause of cancer incidence and mortality.

"This is a disease that is very debilitating since it affects structures of the body that are visible, necessary for communications, and for eating, drinking, and breathing." Bauer said. "Most tumors present at an advanced stage and thus the survival rate is poor."

A Novel Organic Arsenic Molecule: ZIO-101 (S-dimethylarsin-gluthathione): Molecular Biology and Results of a Phase-1 Study in Solid Cancer (Abstract 3188)

It's not a common item in health food stores, but organic arsenic appears to be a whole lot better as an anti-cancer drug than its inorganic cousin, arsenic trioxide. Both arsenics kill cancer cells. The organic version, however, is a kinder, gentler, and more effective molecular weapon against cancer.

"Arsenic is very effective against cancer cells but its inorganic form is toxic at high doses," said Luis H. Camacho, MD, MPH, Assistant Professor, Phase I Program, Division of Cancer Medicine, University of Texas, M D Anderson Cancer Center, Houston, Texas.

"Organic arsenics, in contrast, have similar or better anti-cancer activity and are much safer". Animals tolerate 50 times more organic than inorganic arsenic. Furthermore, organic arsenic is 8 times more likely to get into cancer cells than organic arsenic. This mean organic arsenic may be 100-400 times or greater more effective against cancer than arsenic trioxide.

"Inorganic arsenic can cause heart problems" Camacho said. "This has thus far not been true of ZIO-101 in our study."

Arsenic trioxide is an effective anti- leukemia drug. ZIO-101 has similar effects against leukemia but is also active against other more common cancers. ZIO-101, developed at MD Anderson Cancer Center, combines dimethylarsenic with glutathione, an anti-oxidant complex of 3 amino acids. With it's enhanced ability to enter cancer cells at high concentrations, ZIO-101 increases reactive oxygen species within cancer cells leading to their death.

"ZIO-101 has similar effects to arsenic trioxide in leukemia plus we found it is effective against diverse solid cancers," Camacho said. "It works by activating the cell's apoptotic pathway and killing the cell. Also, because ZIO-101 can be given at substantially higher doses than arsenic trioxide it may use other mechanisms to kill cancer cells."

"For example, when giving ZIO-101 compared to arsenic trioxide, many more arsenic atoms enter each cancer cell even when the extracellular concentration of arsenic is similar" Camacho explained. "This disrupts the mitochondria and kills the cancer cell. Some cancer cells that seem "resistant" to arsenic trioxide are killed by ZIO-101."

ZIO-101 also trips up growth of cancer cells stopping them from dividing. "It paralyzes the cells," Camacho said.

Developing Chemotherapeutics that Target Mitochondria (Abstract 3816) Cancer cells are hungry cells. They are hungry because they are actively proliferating and they expend a lot of energy to duplicate the genetic content and cellular machinery necessary for tumor growth.

Most cells in the body tend to stabilize in an efficient cruise control state where they need less energy to perform their assigned phenotypic tasks, which normally doesn't include dividing and proliferating. Cancer cells are different. They work hard - as hard as other rapidly proliferating cells such as blood cells, the epithelial cells that line the intestine, and skin and hair cells. Proliferating cells crave energy. That hunger may provide two keys to the demise of some cancers, according to Craig B. Thompson, M.D., scientific director of the Abramson Family Cancer Research Institute, University of Pennsylvania.

One key opens the opportunity to target and govern the nutrient regulatory molecular pathways to which cancer cells become addicted.

The other key includes redirecting pharmaceuticals already in use in human patients for the treatment of malaria. Drugs like chloroquine, a standard in the treatment of malaria, are also showing promise in cancer cells that undergo autophagy - or self-digestion in order to gain the energy needed to proliferate.

"By understanding the energy needs of the cell that is growing as opposed to a cell that is not growing, we can very effectively target the metabolism of proliferating cells to develop new cancer therapeutics," Thompson said.

From Thompson's perspective, a critical opportunity for targeting cancer cells with molecular reagents that interfere with cell metabolism resides in a pair of unrelated, independent pathways used by growing cells - either healthy or cancerous - to regulate nutrient uptake.

In normal cells, either pathway is sufficient to maintain the energy demands of growth. If one pathway gets shut down due, say, to a molecular targeting drug, the cell compensates with the alternate pathway for continued function.

In cancer cells, however, the malignancy is often coupled with the 'addiction' of the cell to one of the two molecular governing pathways for energy uptake. By targeting the cancer cell's addiction to a specific molecular pathway governing energy uptake, novel molecular therapeutics can induce cell starvation and death, he said.

"Cancer cells have to become self-sufficient for nutrient uptake," Thompson said. "They need to acquire a mutation in the signaling pathways to regulate nutrient uptake."

Critical molecular targets in two nutrient uptake regulating pathways that Thompson and his colleagues have explored are TOR in the PI3/AKT pathway, and PIM in the Janus Kinase/Stat transcription complexes.

TOR, or target of rapamycin, is activated in the PI3/Akt pathway that primarily controls glucose uptake, but also regulates amino acid uptake. Rapamycin, a peptide isolated from bacteria found in the soil of Easter Island, is prescribed as a therapy for transplant patients and has immunosuppressive activity. It is also under study for cancer treatment and may be particularly effective in cancers that develop addiction to the energy supportive PI3/AKT pathway.

PIM is a component of the Jak/STAT pathway, which is active in a wide variety of cells - especially cytokine producing hematopoietic cells.

"PI3 kinase/AKT pathway, as a group, is probably among the most commonly mutated pathways in human cancer," Thompson said. "For that pathway, we already have a nearly perfect molecular therapeutic. Rapamycin kills that pathway."

While thousands of patients already use rapamycin for immunosuppressive needs after transplant surgery, the opportunity exists to treat cancers that depend on the PI3/AKT pathway for energy needs.

On the other hand, PIM inhibitors may effectively kill the alternative addictive pathway that cancer cells use to provide themselves with adequate energy to proliferate.

"Normal cells don't care if one or the other of these energy regulating pathways is shut down by molecular targeting," Thompson said. "Those cells can compensate with the other pathway, which remains operative. You can shut down one of the pathways, and those normal cells are still somewhat okay."

"In cancer, however, the cell becomes addicted to the one pathway and inhibits the alternate pathway," Thompson said. "So when you suddenly target the pathway that the cancer cell has become addictively dependent upon, the cancer doesn't know how to use the other pathway to compensate."

Since normal cells retain the ability to use either pathway, they escape the targeted inhibition asserted by the TOR or PIM inhibitors. Cancer cells, however, are susceptible to the inhibition imposed by the molecular targeting therapeutics.

Other cancers employ dire means to recruit the raw materials needed as a source of energy to sustain cell proliferation. They sacrifice their own cellular body-parts, Thompson said.

"Autophagy is a process of the cell eating itself to derive enough energy to maintain itself," Thompson explained. "Cells sequester off large parts of themselves essentially to feed growth and proliferation."

The self-sacrifice provides substrates to the mitochondria to convert to available energy in the form of ATP that sustains the cellular mechanisms essential for division.

"It's a recipe for disaster," Thompson said. Cells that consume themselves create excessive amounts of reactive oxidative stress - a molecular event that can promote additional lesions in the genetic code that further facilitates mutations that promote malignancies.

"The nice thing about cells that initiate autophagy is that they are incredibly susceptible to treatment to drugs that inhibit this self-consumption mechanism," Thompson said. The pharmaceutical industry already has a battery of drugs aimed to inhibit autophagic cell behavior.

"Many of the drugs, such as chloroquine, that are anti-malarials inhibit this pathway," Thompson said. "These drugs have been used world wide in millions of human beings for an entirely different purpose. But nobody has used them for cancer therapeutics.

"There are a whole bunch of drugs that we already know are safe in people, but we are just learning how to use them against cancer. They would be important adjuvants in cancer therapeutics.

"These drugs are not magic bullets that are going to make tumors go away, but they are going to work when we find the right way, time, and application for them in the treatment of human cancer," Thompson said.
Founded in 1907, the American Association for Cancer Research is a professional society of more than 24,000 laboratory, translational, and clinical scientists engaged in cancer research in the United States and in more than 60 other countries. AACR's mission is to accelerate the prevention and cure of cancer through research, education, communication, and advocacy. This work is carried out through five major peer-reviewed scientific journals and high-quality scientific programs focusing on the latest developments in all areas of cancer research.

The National Cancer Institute, founded in 1971, is the principal United States government agency charged with coordinating the National Cancer Program. It facilitates international cooperation in clinical trials involving U.S. and foreign collaborating institutions.

The European Organisation for Research and Treatment of Cancer was organized in 1962 to conduct, develop, coordinate and stimulate laboratory and clinical research in Europe, and to improve the management of cancer and related problems by increasing the survival and quality of life for patients.

American Association for Cancer Research

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