Onconase

Quick Summary

Onconase (Ranpirnase) is a chemotherapy drug that demonstrates antitumor activity through cell-cycle interference and apoptosis (cell death). The drug is currently in its third stage of clinical trials to determine if it is a safe and effective treatment method for patients with mesothelioma.

What is Onconase?

Chemotherapy is a class of anti-cancer medications. These medications work to slow or stop cancer cells from replicating and infecting other parts of the body. Due to the invasive nature of mesothelioma, surgical methods are sometimes limited, which means chemotherapy is used widely to treat the disease.

Chemotherapy treatments can vary in many different ways, from how they are administered, how (and how well) they work and their associated side effects. Currently, the first-line of chemotherapy drugs used to treat mesothelioma is a mixture of pemetrexed (Alimta) and cisplatin. This drug combination has a high rate of failure due to chemoresistance (the resistance of treatment in cancerous cells) or the presence of advanced disease. For these reasons, new chemotherapy drugs and treatment combinations are being tested to increase survival rates and life expectancy in mesothelioma cases, one these drugs is Onconase (ranpirnase).

Onconcase is a ribonuclease—an enzyme used to break down RNA (a type of genetic material)  that is derived from early embryos of northern leopard frogs. Onconase is administered through intravenous (IV) to mesothelioma patients who do not qualify for surgical removal of malignant tumors. The drug has been seen to exert antiproliferative (reduced cell replication and spread) and cytotoxic (cell death) effects.

Onconase interferes with cell-cycle regulation, the process by which cells divide their genetic material and replication. It also induces programmed cell death (apoptosis). The drug is currently in its third phase of clinical trials to determine if it a safe and effective treatment method for mesothelioma in comparison to other chemotherapy drugs.

How is Onconase Administered?

Onconase is not currently being used in mainstream chemotherapy treatment for mesothelioma. Its effectiveness in increasing patient survival rate and life expectancy, along with dosing, administration methods and its side effects are being tested in clinical trials.

Onconase is being administered within clinical trials to patients who do not qualify for surgery through intravenous (IV) for 30 minutes. If the disease does not progress, the treatment is administered on a 21-day cycle (every 3 weeks) for at least 6 rounds. Following the 6 rounds, Onconase may be used as a maintenance therapy for patients who are responding well to treatment. Within these treatments, onconcase has been administered with doxorubicin, a commonly prescribed chemotherapy drug for numerous types of malignancies (cancerous tumors), including mesothelioma.

Onconase dosage is being investigated through in vitro (cells that are grown in a lab) and animal model (mice cells) studies. The most commonly used dosage of onconase is between 0 and 20 ml. Within this animal model research, blood work is being conducted before, during and after treatment to monitor the effect of the drug on blood cells along with liver and kidney functions.

How Does Onconase Treat Mesothelioma?

Onconase is currently being tested for widespread use in the treatment of mesothelioma due to its antiproliferative (reduced cell replication and spread) and cytotoxic (cell death) effects.

In particular, onconase has been found to treat mesothelioma in four different ways:

  1. Inhibiting production of NF-κB (a protein complex that causes healthy cells to turn cancerous)
  2. Inhibiting mesothelioma cell invasiveness (ability to spread)
  3. Inducing cell death
  4. Reducing tumor burden (size of the tumor)

Inhibiting Production of NF-κB

Asbestos causes harm to mesothelial cells (a cellular lining found in the chest, abdomen, and heart), which initiated a cellular pathway leading to the secretion of a gene called TNF-α. This gene causes cells to mutate by moving a transcription factor (the script for DNA replication) called NF-κB, which leads to the survival the mesothelial cells but as epithelioid, sarcomatoid or biphasic mesothelioma cell types. Onconase treats mesothelioma by blocking the movement of the NF-κB transcription factor, causing mesothelial cells to die instead of becoming cancerous.

Inhibiting Mesothelioma Cell Invasiveness

Cell invasiveness relates to cell movement and defines its ability to enter the extracellular matrix (the protective barrier) of a neighboring tissue. The invasive nature of a cancer cell can determine how fast cancer is able to spread throughout the body. By blocking NF-κB activity, onconase inhibits MMP9 secretion, a type of protein that is involved in the breakdown of extracellular matrix, effectively inhibiting mesothelioma invasiveness.

Inducing Cell Death

Many chemotherapy drugs cause apoptosis or cancerous cell death. Studies have shown that onconase is able to treat mesothelioma through early and late apoptosis, with increased cell death occurring with increased dosage.

Reducing Tumor Burden

Tumor burden refers to the size of the tumor, or number of cells that make up a particular mass. Studies showed decreased tumor burden when treated with onconase, with tumors from treated mice resuming growth after discontinuation of treatment. This means that onconase has a very strong antitumor effect with these effect lasting long term.

Onconase Drug Combinations

Chemotherapy works best when drugs are given in combination, a technique called combination chemotherapy. Drugs are used in combination as each drug works to treat the cancer cells in a different way. When chemotherapy drugs are combined, doctors are able to administer each drug at its optimal dose, reducing negative side effects and the chance of chemoresistance.

Currently, onconase is being combined with doxorubicin and dihydroartemisinin for mesothelioma treatment. Doxorubicin, a common chemotherapy drug is being combined with onconase in clinical trials. Results from these trials are showing that onconase and doxorubicin is a safe and effective treatment in unresectable mesothelioma, which shows a positive impact on the survival of pretreated patients compared to doxorubicin alone. Onconase and dihydroartemisinin are also being studied through in vitro and animal model research. Results from this drug combination are promising in tumor preventative treatments, which are based on inducing tumors into a dormant state.

Current Onconase Clinical Trials

Clinical trials are used to test the effectiveness and safety of different drugs for various forms of disease. They also give diagnosed individuals a chance to take part in research that has the potential to improve their health and overall disease prognosis.

Clinical trials are done in 4 phases:

  1. Phase 1—Experimental drug is tested on a small group of people for the first time to test its safety and any possible side effects.
  2. Phase 2—Drug is given to a larger group of people to gain data on the effectiveness of the drug on a particular disease or condition.
  3. Phase 3—Drug is given to even larger groups to confirm its effectiveness.
  4. Phase 4—Done after the drug is approved and on the market to gather information on its long-term benefits and risks.

Onconase has been used in phase 1 and phase 2 mesothelioma trials and is currently in phase 3. This randomized phase 3 trial is comparing the effectiveness of onconase and doxorubicin versus doxorubicin alone in treating patients aged 21 and older with mesothelioma. Results are showing that combining onconase and doxorubicin may lead to improved survival rates in patients diagnosed with mesothelioma.

As part of the confirmatory stage of phase 3, the Food and Drug Administration (FDA) has given onconase orphan drug status—a designation that permits Alfacell (the company running the clinical trial) to be awarded seven years of marketing the drug for treatment of malignant mesothelioma.

Onconase Side Effects

As with all chemotherapy drugs, onconase can cause negative side effects. But the effects are considered common when compared to other drugs. There is a chance that some patients may experience severe side effects, and in these cases, patients should inform their doctors immediately. Because of cytostatic function (inhibition of cell growth and death) onconase is showing minimal side effects as it does not affect healthy cells.

There are no current clinical trials where onconcase is being administered on its own. In the phase 3 clinical trial described above, when combining onconase and doxorubicin, the most common sides effects patients experienced included weakness, chills, weight loss, partial or total loss of muscle movement, and diarrhea. Further side effects may be observed as onconase continues to be studied.

For more information on Onconase clinical trials, contact our Patient Advocates today.

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Sources
  1. Oncogene, “Onconase mediated NFKβ downregulation in malignant pleural mesothelioma”
    Retrieved from: https://www.nature.com/articles/onc2010643. Accesses on February 24, 2018.
  2. Genes and Cancer, “Ranpirnase Interferes with NF-κB Pathway and MMP9 Activity, Inhibiting Malignant Mesothelioma Cell Invasiveness and Xenograft Growth.”
    Retrieved from: https://www.ncbi.nlm.nih.gov/pubmed/21901170. Accesses on February 24, 2018.
  3. US National Library of Medicine—ClinicalTrials.gov, “ONCONASE Plus Doxorubicin”
    Retrieved from: https://clinicaltrials.gov/ct2/show/NCT00003034?term=onconase&cond=Mesothelioma&rank=1. Accesses on February 24, 2018.
  4. Acta Biochim Biophys Sin (Shanghai), “Combination of onconase and dihydroartemisinin synergistically suppresses growth and angiogenesis of non-small-cell lung carcinoma and malignant mesothelioma.”
    Retrieved from: https://www.ncbi.nlm.nih.gov/pubmed/27590062. Accesses on February 24, 2018.
  5. Journal of Clinical Oncology, “Randomized, multicenter phase III study of ranpirnase plus doxorubicin (DOX) versus DOX in patients with unresectable malignant mesothelioma (MM)”
    Retrieved from: http://ascopubs.org/doi/abs/10.1200/jco.2009.27.15_suppl.7507. Accesses on February 24, 2018.

Last modified: May 7, 2018