Emerging cancer therapies and novel targets

Oct 25 2007

What are the cancer drugs of tomorrow and how will they be developed? At the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics, researchers will present some answers to these and other pressing questions regarding emerging cancer therapeutics.

New targets, such as cell signaling receptors found on cancer tumors, provide tantalizing targets for engineered antibodies and small inhibitory molecules. New therapeutic technologies, such as virus-based therapy against cancers metastasized to nerve cells and a unique two-headed antibody that attaches killer T cells to tumor cells, offer promising methods for controlling disease.

A team of researchers from Cancer Research Technology based at University College London report for the first time CRT0059359, a small molecule inhibitor of protein kinase D (PKD), a key part of a chemical signaling pathway that is disrupted in a variety of cancers, including pancreatic cancer.

Thought to be involved in a number of cellular processes, PKD plays a vital role in cell division signaling leading to tumor cell proliferation, and in apoptosis, or programmed cell death.

“We think this is the first viable protein kinase D inhibitor that has come to light – and our studies using this molecule validate protein kinase D as an anti-cancer target,” said lead researcher Lloyd Kelland, Ph.D., D.Sc., head of biology at Cancer Research Technology. “In cell and animal models of pancreatic cancer, this particular molecule appears to effectively induce apoptosis.”

According to Kelland, their previous studies demonstrated that blocking the gene that produced PKD drastically reduced the survival of a human pancreatic cell culture. To find an effective inhibitor for PKD, the researchers initially screened over 65,000 molecules to determine if any of them blocked the function of the protein.

Following chemical refinement of molecules found in the screen, only CRT0059359 had the appropriate chemical properties for testing for anticancer activity in animal models of cancer.

Exposure of pancreatic cells to CRT0059359 showed a marked decrease in cell proliferation and increase in apoptosis. Studies using a mouse model of pancreatic cancer indicated that CRT0059359 demonstrates a reasonable reduction of tumor growth without causing harm to healthy cells. “More importantly, this particular molecule isn't our final candidate, yet, as we are refining its chemical structure to improve bioavailability and increase potency,” Kelland said.

Nerve-sparing therapy with oncolytic herpes virus for cancers with neural invasion: Abstract PR 8.

A cancer-targeting herpes virus could effectively stop the spread of cancer to the nervous system, preventing paralysis according to a report presented by researchers from Memorial Sloan-Kettering Cancer Center. Their study, funded by the National Institutes of Health, demonstrates that the oncolytic (cancer-killing) virus is safe in an animal model of human cancer and selectively targets cancer cells without damaging nerves.

Neural invasion, the movement of metastasized cancer into nerves, is a debilitating feature of many forms of spreading cancer, especially in prostate, head and neck, and pancreatic carcinomas. Treatment for neurally invasive cancer includes resection – the physical removal of the cancer cells through surgery – which often damages the nerve, leading to loss of function. Approximately 25 percent of all prostate cancers cases, for example, spread to nerves, and surgery to remove them often leads to erectile dysfunction and incontinence.

“The invasion of cancer cells along nerves is generally linked with poor outcomes for patients, and can have awful consequences for patients even when it is successfully treated,” said Ziv Gil, M.D., Ph.D., a researcher at Memorial Sloan-Kettering Cancer Center. “By modifying a virus that is naturally attracted to nerves, it can serve to target and kill cancer and prevent healthy nerves from being damaged.”

In the study, Dr. Gil and his colleagues worked with a genetically engineered herpes simplex virus called NV1023, which had been rendered non-virulent by removing the gene that allows the virus to attack healthy cells. For reasons that are still not entirely clear to researchers, the virus is lethal to cancer cells, despite the fact that it ignores healthy tissue.

The researchers demonstrated that the virus effectively killed cells from three human carcinoma cell lines: pancreatic, head and neck, and prostate cancer. In addition, using a novel animal model, the researchers demonstrated that a single injection of an attenuated (non-virulent) herpes virus can effectively treat nerves infiltrated by cancer, while preserving physiological nerve function. Remarkably, all of the un-treated animals with cancers developed complete nerve paralysis within five weeks, whereas most of the NV1023 treated animals had intact nerve function up to 14 weeks after treatment. Phase I studies of the attenuated virus in humans are underway.

AR36A36.11.1, a monoclonal antibody targeting CD59, enhances complement activity and exhibits potent in vivo efficacy in multiple human cancer models: Abstract A 70.

Scientists at ARIUS Research, Inc., a biotechnology company based in Toronto, Canada, have discovered a potential therapeutic that foils cancer cell's ability to hide from the immune system. According to their findings, the antibody, termed AR36A36.11.1, allows the immune complement system – protein complexes that recognize and kill foreign cells – to target and kill tumors by rupturing their membranes. AR36A36.11.1 activates complement activity against cancer cells and inhibits tumor growth in mouse models of breast, colon, lung and prostate carcinomas, the researchers say.

“While tumors can present markers that indicate they are diseased, they often evade the innate immune system by producing an excess of CD59, a surface protein that prevents the assembly of complement proteins on the outside of tumor cells,” said Baldwin Mak, Ph.D., a research scientist at ARIUS. “Through the inhibition of CD59, we can disrupt a cancer cell's ability to keep the immune system from poking holes in its membrane.”

According to Mak, the CD59-inhibiting antibody was discovered through a technique developed at ARIUS called “FunctionFIRST™,” a methodology that screens antibodies for cell killing effects rather than creating antibodies that bind a specific target. After AR36A36.11.1 proved effective at killing cultured cancer cells, the researchers tested the molecule in animal models of adenocarcinomas. “Subsequent analyses revealed the mechanism of action – the antibody binds to a region on CD59 that inhibits formation of membrane attack complexes, which form pores that cause cell lysis,” said Mak.

When administered in mice once a week for eight weeks, AR36A36.11.1 inhibited breast cancer tumor growth by 100 percent. Mouse studies also revealed that the antibody could halt the growth of prostate tumors by 86 percent, lung tumors by 58 percent and colon tumors by 48 percent, said Mak.

“Our studies seem especially promising in breast cancer models, where CD59 inhibition by the antibody appears to cause complete tumor regression at all dose levels,” said Mak. In particular, this potent effect is observed in a breast cancer model that represents a patient population that cannot be treated by Herceptin, the only therapeutic antibody approved for breast cancer treatment.

A humanized AR36A36.11.1, suitable for clinical studies, has been made and the researchers are preparing to test this antibody in clinical trials.

AR47A6.4.2, a functional naked monoclonal antibody targeting Trop-2, demonstrates in vivo efficacy in human pancreatic, colon, breast and prostate cancer models: Abstract PR 12.

A newly generated antibody has been found to be effective against an array of human cancers –including those of the pancreas, colon, breast and prostate – report researchers from ARIUS Research, Inc., a biotechnology company based in Toronto, Canada.

According to the researchers, the antibody, AR47A6.4.2 targets Trop-2, a protein found on the surfaces of cells and thought to be a key part of the expansive MAPK pathway, an enzymatic cascade crucial for the control of a cell's life cycle.

ARIUS researchers report that the antibody has a significant anti-tumor effect in a mouse model of human pancreatic cancer, greatly extending the lifespan of the mice. Subsequent testing showed efficacy in mouse models of breast, colon and prostate cancers. The antibody inhibited tumor growth by 100 percent in a pancreatic cancer model, 90 percent in a breast cancer model, 60 percent in a colon cancer model and 61 percent in a prostate cancer model, the researchers report.

“Trop-2 is a novel target – a protein that has been implicated in the cancer literature as related to very aggressive cancers, but its exact function has not been clear,” said Amandine H.L. Truong, Ph.D., a research scientist at ARIUS.

According to Truong, the antibody that bound to Trop-2 was discovered through a technique developed at ARIUS called “FunctionFIRST™,” a process that works in reverse of traditional methods for generating antibodies. Most research in targeted therapeutics involves generating antibodies based on known targets. Through the ARIUS method, researchers generate effective antibodies first, before screening them against cancer cell samples to select the most potent ones. Only through later analysis do they discover the exact targets of the antibodies.

ARIUS researchers are currently preparing for clinical trials with a “humanized” form of the antibody.

Highly efficient elimination of melanoma cells expressing melanoma-associated chondroitin sulfate proteoglycan (MCSP) by MCSP/CD3-bispecific chain antibody constructs: A 61.

An engineered antibody-like molecule that binds skin cancer cells to killer T cells, literally tying melanomas to the immune system, could provide a novel therapy for the disease, according to researchers at Micromet, a biotechnology company based in Bethesda, Md., and Munich, Germany. Melanomas are particularly sensitive to T-cell therapies, the researchers say, and their novel antibody construct could be a means of engaging some of the most effective cancer-killing cells in the immune system's arsenal.

These agents are new class of artificial antibodies – what Micromet researchers term a BiTE class (for bispecific T-cell engager) – that are T cell-recruiting antibodies.

Essentially, the researchers have linked the binding regions of two specific antibodies together with a short peptide chain.

In this case, one antibody binds to an activating receptor on the surface of killer T cells, called CD3, and the other binds to a protein generally found on the surfaces of skin cancers, called melanoma-associated chondroitin sulfate proteoglycan (MCSP).

“Unlike regular monoclonal antibodies used in cancer therapies, BiTE antibodies can recruit killer T cells for redirected lysis of tumor cells,” said Roman Kischel, M.D., director of immunotherapy at Micromet. "By this approach only cells expressing the antigen are attacked by T cells, and we can see target cell lysis at very low picomolar concentrations of BiTE antibodies.”

When MCSP-BiTE binds to cancer cells, the cells become visible for any killer T cell passing by. “The T cell will briefly attach to the BiTE-decorated cancer cell and inject its deadly cocktail of killer proteins into the tumor cell,” Dr. Kischel said. “This event gears up the T cell to produce more killer proteins and to go into melanoma serial killing mode.”

According to Dr. Kischel, the BiTE antibodies do not require specific killer T cells, which may circumvent many limitations of T-cell therapies, such as the mechanisms that some tumors use to escape the immune system and defects in the ability of immune cells to recognize antigen, a frequent problem among cancer patients. Even on the cellular scale, BiTE antibodies are tiny, about a third of the size of conventional antibodies, which Micromet researchers believe may aid by improved tumor penetration in the effectiveness of the therapeutic.

Currently, Micromet researchers are studying similar antibodies specific for B-cell lymphomas in a Phase I trial. The MCSP-BiTE antibodies are now undergoing preclinical studies in cell cultures and animal models.