A classic drug could become our cheapest and safest new cancer drug.

When you think of drugs used to treat cancer, you often think of drugs that are expensive that attack not only the cancer cells but also your own cells. They often cause severe side effects and aren’t always effective. There is a class of very common and relatively inexpensive drugs, however, that are showing promise in their ability to treat tumor cells.

 

Bisphosphonates are a very common class of drug that are often prescribed to treat osteoporosis. They work by inhibiting osteoclasts that break down bone into minerals to be used by the body. Another property of bisphosphonates that is being investigated is their effect on tumor cells. They have shown evidence to work against tumor cells in five different ways. They can trigger tumor cells to undergo apoptosis, inhibit tumor cell adhesion, and prevent tumor angiogenesis or blood vessel development. In addition to these direct effects on tumor cells, bisphosphonates can help the body better defend against the tumor cells by inhibiting macrophages produced by the tumor as well as activating a certain class of cytotoxic T-cells. Lastly, bisphosphonates exhibit a synergistic relationship with a number of anti-tumor drugs, providing an opportunity for them to be added to cancer patients’ existing medication regimens.

 

These properties of bisphosphonates are exciting and worth devoting more time and money into researching them. A cheap, and safe drug that can be used to treat cancer could be a potential breakthrough in the complex and expensive field of oncology. With more research, we could very well see bisphosphonates as a part of every cancer patient’s medication regimen.

 

Acker, H. H., Anguille, S., Willemen, Y., Smits, E. L., & Tendeloo, V. F. (2016). Bisphosphonates for cancer treatment: Mechanisms of action and lessons from clinical trials. Pharmacology & Therapeutics, 158, 24-40.

 

 

A Look into Neoadjuvant Trial Design and It’s Potential for Anticancer Drug Development

There is a very low success rate among anticancer agents in the drug development process, particularly between stage 2 and 3 clinical trials.  There is a noticeably lower success rate for oncology drugs to progress from one clinical trial to the next (57%) as compared to non-oncology medications.  Researchers at the Sloan Kettering Cancer Center in New York attempted to look for possible explanations for the phenomenon.  What they hypothesize is that the ability of clinical trials to predict the efficacy of novel drugs is inaccurate due to the outdated methods of determining end point response in solid tumors.  They assert that the current methods used, most notably the Response Evaluation Criteria in Solid Tumors (RECIST), were developed decades ago using arbitrary methods of grading tumor response that were never intended to be used for clinical significant outcomes.

The researchers suggest that improvements in the drug development process should start by using efficacy grading techniques that were intended for clinical outcomes, and are reflective of current capabilities in medical imaging.  The recommendation that they make involve using pathological complete response (pCR), which takes into account the effects that drugs have on metastatic cancer cells rather than just the impact on solid tumor tissue cells. This method is currently used for neoadjuvant trials, and could be used to predict improvements in overall survival for novel drug compounds.  In a review of numerous clinical studies the authors found usage of pCR methods in neoadjuvant methods to determine efficacy correlated to improved survival outcomes in breast cancer, muscle-invasive bladder cancer, and Non-small cell lung cancer.

The FDA has already approved pCR as a relevant indicator of neoadjuvant efficacy and as a surrogate indicator of increased survival in some breast cancer patients.  However, it is possible that this modern means of assessing cancer response could lead to an increase in the approval of new cancer drugs based on better ability to measure cancer response in patients.  The question that remains is: does this new method of efficacy evaluation seem like it will increase options for oncologists to improve survival rates, or is it possible that it will lower standards of approval to the detriment of cancer patients?

 Article Link

Funt, S. A., & Chapman, P. B. (2016). The Role of Neoadjuvant Trials in Drug Development for Solid Tumors. Clinl Cancer Res. 2016; Published OnlineFirst February 3, 2016; doi: 10.1158/1078-0432.CCR-15-196.

Potential Bias of Speakers on Behalf of New Cancer Drugs

The number of cancer cases throughout the world is clearly on the rise, requiring an ever increasing need for a cure and more effective treatments. Many speculate that a cancer cure has already been discovered but it is being hidden because of all the money cancer as a disease generates. Others question why cancer is so prominent now but was not spoken of this often in their childhood. With so much confusion abound about the treatment of cancer and its widespread effects, an article delving a little into the processes of the FDA when it comes to cancer and possible conflicts of interest may be helpful.

The authors of this article decided to search into the meetings held by the Oncologic Drugs Advisory Committee, the advising committee to the FDA concerning cancer treatments, to determine what other influences may be at play when deciding if a drug should go to market. They reviewed twenty-eight meetings between 2009 and 2014. The main investigation for this study was to determine what biases may be present within these extra speakers, who usually have taken the drug discussed or represent an organization. The researchers recorded what the speakers’ affiliations may be as well as their financial association or lack thereof.

It was found that amongst the 103 speakers present at the 28 meetings, 58 were representing an organization associated with the type of cancer being potentially treated, 46 were diagnosed with the specific type of cancer, and 31 had taken the drug. Almost all of the speakers throughout these twenty-eight meetings (92%) supported the approval of the drug. Thirty percent of the speakers revealed that they did indeed have financial associations with the company seeking approval while two speakers did have associations but did not disclose them when asked.

The authors concluded that the FDA committee should consider possible financial associations and personal biases of speakers when reviewing a cancer drug company’s marketing approval. When we look at how huge of a problem cancer has become and how much it could affect both us and those around us, does this potential bias matter so much? If the drug trials show that the drug works, should a small financial association hold this FDA committee back from approving their marketing?

Reference: Abola MV, Prasad V. Characteristics and conflicts of public speakers at meetings of the Oncologic Drugs Advisory Committee to the US Food and Drug Administration. Jama Intern Med. Published online February 1, 2016. Accessed February 6, 2016.

Novel Drug Therapy for Treatment of Relapsed Chronic Lymphocytic Leukemia

Chronic Lymphocytic Leukemia (CLL) is the most prevalent leukemia among adults. It is also one of the most commonly relapsing types of cancer. While chemotherapy and traditional forms of cancer treatment do prolong remission and overall survival rates, relapse occurs in practically all patients. The commonality of relapse in patients with CLL has prompted the discovery of novel drug targets in hopes of stopping the proliferation of leukemia cells in the body. Bruton’s tyrosine kinase (BTK) is a downstream signal proliferator in several pathways that are relevant to both tumor-cell survival and the ability for the tumor-cells to adhere to one another.

However, the inhibition of BTK results in the loss of immunoglobulins in blood serum which results in an increased risk of infection for those affected by BTK inhibitors. In addition, because the structure of BTK is vastly different from other tyrosine kinases it is a perfect therapeutic target. Ibrutinib is a first-in-class, small molecule drug that covalently binds to and inhibits the action of BTK, specifically its cysteine (C481) site. Ibrutinib is, however, not a very selective inhibitor as it also inhibits the action of many other protein kinases and causes severe side-effects. Second generation BTK inhibitor, acalabrutinib, is highly selective to BTK C481 and therefore has a lower side-effect profile than ibrutinib.

The response to acalabrutinib in early clinical testing was overwhelming with 98% of patients having reduction in lymphadenopathy (swollen lymph nodes) and 61% having concomitant lymphocytosis (elevation in blood-lymphocytes). Additionally, most adverses effects of the medication were not considered dangerous or life-threatening with most being mild headaches and diarrhea. Only two events of progression were reported in the study. All in all, acalabrutinib shows major steps in the reduction of relapses for CLL patients, and a new string of hope for those diagnosed with CLL.

Do you think this drug has the potential to become a first like treatment for leukemias? Could drugs like this lead to the end of chemotherapy?

 Article Link

Citation:

Byrd JC, Harrington B, et al. Acalabrutinib (ACP-196) in Relapsed Chronic Lymphocytic Leukemia. N Engl J Med. 2016;374:323-332