Will Apoptosis Succeed Where Other Cancer Treatments Haven't? Three Companies Trying

Includes: BLRX, CRIS
by: Andreas Spiro

The Big Four: Autologous Vaccines, TKI's, Monoclonal Antibodies, and Apoptosis

Autologous cancer vaccines are understandably the talk of the oncology town. Indeed, I have covered several companies undergoing various clinical trials attempting to activate the human immune system against cancer using a patient's own immune cells. The idea of activating the body's natural defenses against the disease without external drugs is conceptually attractive and definitely warrants investor attention.

However, while it is not indicative of the future and I do believe more than one company will soon break through on a successful autologous cancer vaccine, no one can deny the simple fact that so far, they have not succeeded as a class. The only FDA approved autologous cancer vaccine remains Dendreon's (NASDAQ:DNDN) Provenge. For three and a half years it has maintained its singular status as the only regulatory success story in that sphere, though not yet a commercial one.

Though the idea of activating the immune system against cancer with a patient's own cells is attractive, the difficulty in following through on it can be reasoned by the simple fact that cancers that are not naturally detected by the immune system are not detected for good reason. To change that reality is proving quite difficult. The main advantage of an autologous vaccine is its non-toxicity coupled with immune memory, it being of the patient's native cells. This is as opposed to the presently more successful monoclonal antibody approach in which foreign antibodies are injected to trigger a systemic immune response. This can result in serious side effects, even death in some cases, whereas it is generally conceded that the chances for serious side effects for autologous cancer vaccines are nil.

Until the autologous cancer vaccine space gets its act together, which I believe it will, there are three other main classes of cancer treatments out there besides chemotherapy. Two have met decent levels of success. These are TKI's and monoclonal antibodies. TKI's seeks to block an enzyme called tyrosine kinase, which is a major factor in cancer cell growth. Every drug that ends with -nib is a TKI inhibitor. The most famous TKI inhibitor to be approved was Novartis' Gleevec (imatinib) in 2001, and was so successful it was nicknamed the "miracle drug".

The problem with TKI's, however, is side effects. Many TKI's like Glaxo's (NYSE:GSK) Taflinar, approved this year, can cause new cancers to develop (page 21). Another, Mekinist, can cause heart failure (page 20). As for monoclonal antibodies (all drugs with the suffix -mab), they can also cause serious side effects as they can trigger overreaction of the immune system. For example, Bristol Myers' (NYSE:BMY) Yervoy (ipilimumab) had 10% of patients drop out due to serious side effects during its phase III trial, though it was still approved.

This leaves apoptosis. What is apoptosis? It literally means cell suicide. Cells in all living things have a finite lifespan, at the end of which, all cells die. In humans, cells die in one of two ways. The first is necrosis. Necrosis occurs when some form of external force like poison or injury damages the cell in question. It can be thought of as the metaphorical murdering of the cell. The second is apoptosis. Apoptosis occurs when cells die as a response to internal triggers. One example is the recognition of a virus, upon which the cell commits suicide in order to avoid being infected and being forced to replicate the virus.

The process can be broken down into four distinct stages. The first stage happens in response to the trigger, and involves a type of protein called a caspase being activated inside the cell, which starts to break down its internal structure. This causes the cell to shrink, and turn into what are known as blebs. Caspases also stimulate the production of enzymes called DNases. During the second stage, these DNases break down the nucleus inside the cell, and the cell emits a signal that summons a particular type of white blood cell called a macrophage. In the third stage, the rest of the cell breaks into small pieces that are then, in the fourth stage, absorbed by the macrophages and removed from the body.

Apoptosis and cancer

Caspases are proteins that promote cell death. The opposite of these are proteins that promote cell survival. Cancer cells hold an abundance of survival promoting proteins, and so resist apoptosis. This enables the cells to continue living and reproducing, and is one of the primary factors behind the spreading of cancer cells, as well as their resistance to treatment. If apoptosis could be induced in cancer cells then, despite their abundant store of antiapoptotic proteins, the cancer cells would die and be removed from the body by the macrophages. An example of this in action can be found in this study, in which a death promoting protein called Nur77 induced apoptosis in a particular type of cancer cell that contained an overabundance of a survival promoting protein called Bcl-2. Bcl-2 is overexpressed in a wide variety of cancers, including leukemia and lung, liver, gastric, ovarian, prostate, and breast cancers.

Treatment in this manner holds many advantages over traditional and highly toxic cancer therapies. The beauty of apoptosis cancer treatment is that, in many cases, the proteins these treatments are seeking to block are unique to cancer cells. This means that apoptosis treatments could be targeted.

Therapy using apoptosis-inducing drugs could serve to reduce the dosage of chemotherapy and radiation required to kill cancer cells, as well as vastly improve the targeting of cancer treatment. This, in turn, could dramatically reduce the side effects that inhibit the efficacy of the current standard of care. A number of companies are currently working on the induction of apoptosis in cancer cells, the following of which have upcoming catalysts.

Curis, Inc. (CRIS)

The first is Curis. Curis' pipeline includes a range of cancer treatment types, one of which it calls CUDC-427. CUDC-427 inhibits IAP, which is a survival promoting protein short for Inhibiting Apoptosis Protein. This is a protein used specifically by cancer cells to avoid cell death, making its inhibition targeted to cancer. Once IAP is inhibited, apoptosis is triggered in the cell.

Curis licensed CUDC-427 from Genentech, a member of the Roche Group, in November last year. To date, two phase I clinical trials have been carried out; one by Genentech in 2010 designed to study CUDC-427's effect on mucosa-associated lymphoid tissue (MALT) lymphoma patients, and one initiated in June this year by Curis, designed to study CUDC-427's effect on refractory solid lymphoma patients. The Genentech trial results were presented in June this year, at the annual meeting of the American Society of Clinical Oncology. Results were encouraging, including complete responses in a patient with ovarian cancer and a mucosa-associated lymphoid tissue lymphoma patient, and are the basis of the second Curis-run trial.

Catalysts include the initial results of ongoing current phase I trial, due in July 2014, and the initiation of at least two additional studies in 2013 or early 2014, designed to determine CUDC-427's effect on both breast cancer and MALT lymphomas.

BioLineRx, Ltd. (NASDAQ:BLRX)

The next on the list is BioLine. BioLine is a little farther down the line in terms of development of its apoptosis treatment than Curis, the focus of which is a peptide called BL-8040. BL-8040 functions as an antagonist of CXCR4, a survival promoting protein directly involved in tumor progression and cancer cell survival.

BL-8040 is currently undergoing a phase II study of 50 patients, designed to evaluate the safety and efficacy profile of escalating doses of BL-8040 patients with acute myeloid leukemia (AML). The primary endpoints of the study are the safety and tolerability of BL-8040. Secondary endpoints include the pharmacokinetic profile of the drug and an efficacy evaluation.

While the results of the trial are not expected until 2015, a number of recent catalysts have driven up company's stock price and could continue to do so between now and then. These include BioLine's announcement that BL-8040 has been shown in pre-clinical trials to be effective for the treatment of thrombocytopenia in August this year, and the announcement that BL-8040 has been granted Orphan Drug Status by the FDA.

Senesco Tech (SNTID)

Another one to watch is Senesco. A fellow SA author wrote an exhaustive piece about this company back in August for those interested in a fuller picture. The company focuses exclusively on its candidate SNS01-T. SNS01-T works in a similar way as those described above, however it suppresses two survival-promoting proteins called NF-kB and ICAM. SNS01-T also acts to block what's called the IL-6 paracrine, which in simple terms means it stops a tumor from getting any bigger. The treatment has also been granted Orphan Drug Status by the FDA, and is currently undergoing Phase Ib/IIa clinical study at a number of sites. Senesco expects to complete the study as early as January 2014, less than 3 months away.


This article was meant as an introduction to apoptosis as a promising approach to cancer treatment. The apoptosis space has received less coverage than TKI's, monoclonal antibodies, or autologous cancer vaccines, though it deserves serious consideration for its targeted nature. Investors should do their own due diligence as to whether or not any company focusing on apoptosis warrants investment at present. As clinical trials are completed, we will see the side effect profile of this approach take shape, and whether apoptosis has advantages over the other three approaches.

Disclosure: I have no positions in any stocks mentioned, and no plans to initiate any positions within the next 72 hours. I wrote this article myself, and it expresses my own opinions. I am not receiving compensation for it. I have no business relationship with any company whose stock is mentioned in this article.