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By Robert G. Bell

Robert BellAnother aspect of targeted cancer therapy is protein therapy. Protein therapy is a regimen intended to deliver a healing protein that is absent in a diseased patient. On paper, protein therapy would appear to be ideal for the cancer patient—an agent that facilitates site specific cancer apoptosis with little to no side effects. Imagine if we could add a protein, a new one or one that may be deficient in a cancerous state, that would prevent metastasis and facilitate cancer cell death. In reality, it can be difficult to deliver the optimal dose of the intact protein to the site of action within the cancer cell. Regardless, protein therapy will continue to evolve as cancer therapy, both as an individual agent and in combination with other cancer treatments (e.g., surgery, radiation, chemotherapy). 

One such therapy involves a protein therapy that has the potential to prevent metastasis in breast and ovarian cancers. Last year, a team of Stanford scientists engineered a protein, without side effects, to act like a decoy protein to prevent metastatic signaling between Axl and Gas6 proteins. In animal studies, mice with an aggressive form of breast cancer and ovarian cancer had 78% and 90% respectively fewer metastatic nodules than untreated mice. To generate and engineer the protein, the Stanford research team used high-throughput screening to evaluate over 10 million Axl variants to find a variant that bound tightly to Gas6. Axl has two related proteins, Mer and Tyro3, that can also promote metastasis and are also activated by Gas6, opening up the possibilities of multiple sites of beneficial action and therapy.

Another interesting protein therapy involves generating the protein that allows cancer cells to proceed to apoptosis. A team of researchers at Okayama University identified the REIC/Dkk-3 gene as a gene whose expression is reduced in many human cancers such as prostate, bladder, testicular, and lung. When the researchers forced the expression of REIC/Dkk-3, it induced apoptosis in human prostate cancer cell lines lacking endogenous REIC/Dkk-3 expression but not in REIC/Dkk-3-proficient normal prostate epithelial and stromal cells (the apoptosis involved c-Jun-NH2-kinase activation, mitochondrial translocation of Bax, and reduction of Bcl-2). A single injection of an adenovirus vector carrying REIC/Dkk-3 showed a dramatic antitumor effect on a xenotransplanted human prostate cancer and could be a novel target for protein therapy of prostate cancer.

Another interesting immunotherapy is checkpoint inhibitors. Immune checkpoints, as the name implies, keeps the immune system in a balance with costimulatory and inhibitory signal checks. Immune-checkpoint proteins and signaling can be disrupted by tumors allowing an immune resistance mechanism to the tumors, allowing immunologic escape of the cancer antigens. Therapies to prevent this disruption are under development. One cancer in which checkpoint inhibitors is generating excitement is metastatic renal cell carcinoma. A promising candidate is nivolumab, which is an inhibitor of checkpoint protein programmed cell death protein 1 (PD-1) and is now in phase III clinical trials for the treatment of metastatic renal cell carcinoma. The use of these “softer” cancer immunotherapies such as cancer vaccines, protein therapies and check point inhibitors maybe able to compliment and add to conventional cancer chemotherapy and one day may offer safe and efficacious first line precision treatment alternatives to conventional cancer therapies.

Robert G. Bell, Ph.D., is president and owner of Drug and Biotechnology Development LLC, a consultancy to the pharmaceutical industry and academia for biological, drug, and device development.