Oncology Highlights - November 2016
Reading our newsletter will only take a few minutes and allows you to keep up to date with last month’s news items on oncology drug development.
Kind regards, the SMS-oncology team
Chronic jet lags induce liver cancer?
In less than 40 years the incidence of the most common type of liver cancer, hepatocellular carcinoma (HCC), has nearly tripled. Although it is uncertain what causes most liver cancers, among the risk factors are cirrhosis, hepatitis B or C infections, and lifestyle factors such as alcohol use and obesity. Obesity related liver disease is even believed to be one of the leading causes of the increasing incidence of HCC. Now, researchers of the Baylor College of Medicine found that another lifestyle factor also affects normal control of liver metabolism: repeated induced jet lags. By examining mice, it was found that disruption of the circadian clock activates two nuclear receptors which regulate liver bile metabolism; the bile acid receptor FXR and xenobiotic receptor CAR. These mice developed fatty liver disease, which progressed to chronic inflammation and eventually liver cancer in some cases. Although the scientists did not directly study a correlation in humans, there is evidence that sleep disruption has the same effects in humans. The team published their results in Cancer Cell and believe that circadian dysfunction is an independent risk factor of HCC, and restoration of bile acid homeostasis and inhibition of CAR could be promising treatment options.
Smoking results in 150 new mutations per cell in your lung
For decennia it has been known that smoking tobacco is linked to cancer, although the underlying mechanisms how tobacco smoke damages the genome and creates mutations causing cancer are still not fully understood. A recent study published in Science performed a genetic analysis of 5,243 mutational signatures and DNA methylation changes from 17 different cancer types linked to smoking. The researchers found that the yearly damage in your DNA when smoking a pack-a-day comes down to 150 new mutations per cell in your lungs. Also the larynx, pharynx and oral cavity were affected, with 97, 39 and 23 new mutations respectively. Furthermore, the team found 20 distinct cancer genome sequences, or “mutational signatures”, of which 5 were more commonly found in smokers vs non-smokers. One of the signatures is mainly found in cancers derived from tissues directly exposed to tobacco smoke in which the known carcinogen benzo[a]pyrene attributes to misreplication of DNA (DNA nucleobase change; adenine (A) instead of cytosine (C)). Other signatures are likely to reflect indirect activation of DNA editing by a “internal clock speeding” process: the faster a cellular clock runs, the more chances the DNA in the cell has to mutate. The results support the motion that smoking elevates cancer risk by increasing the somatic mutation load.
First CRISPR gene editing tested in humans
For the first time, scientists from the Sichuan University in Chengdu (China) injected a person with cells that contain genes edited using the revolutionary CRISPR–Cas9 technique. In this clinical trial, researchers collected the immune cells from a non-small cell lung cancer (NSCLC) patient, used CRISPR-Cas9 to disable a gene coding for the protein PD-1, and then gave the edited cells back to the patient. PD-1 normally halts the cell’s immune response; a function cancers take advantage of to proliferate. Injections were supposed to be given earlier this year, but the date was pushed back as it took longer than expected to culture and amplify the cells. Being a simpler and efficient technique, CRISPR will probably accelerate the race to get gene-edited cells into the clinic, claims Carl June, the leader of one of the earlier studies. Scientists from the Peking University aim to start clinical trials using CRISPR against bladder, prostate and renal-cell cancer in early 2017, though these trials have no approval yet, nor do they have funding.
Genetic explanation for higher incidence of cancer in males than females
Scientists of the Dana-Farber Cancer Institute in Boston think to have found a genetic explanation why cancer is more common in males than in females. They found that an extra copy of certain protective genes in the cells of females give an extra line of defense against the cells growing out of control. These duplicates are likely to be one of the reasons of the imbalance, including up to 80% of the excess male cases in some tumor types, the study reports. Author Andrew Lane: "Data from the National Cancer Institute show that males carry about a 20 percent higher risk than females of developing cancer. That translates into 150,000 additional new cases of cancer in men every year." Back in the days, the difference was explained by the fact that men more often smoke and work in harmful environments but nowadays this explanation is brushed aside as the above-mentioned patterns have changed. The genes they found to be more often mutated in males are exclusively on the X chromosome, which is compelling evidence of their theory, Lane said. The working copies of these genes in female cells might explain the lower incidence of many cancers in women.
Leukemia testing breakthrough by student project
Something that started as a summer project for high school and college students resulted in a new diagnostic tool for chronic myeloid leukemia (CML). With the new test, CML can now be diagnosed using dried blood spots; only a few small spots have to be collected on a paper card and mailed to a center for diagnosis. The test offers an inexpensive and easy alternative to whole blood tests that have to be shipped to diagnostic labs. The students found a solution for one of the major hurdles for a simpler test, namely using special paper that is not so acidic or starchy to avoid the detecting RNA markers from degradation. CML is often diagnosed late in poor countries, resulting in high death rates, partially due to the fact that these countries cannot afford the expensive shipments to Europe or US. The first test run was positive; cards sent from Africa and Asia were still useful after heat, cold and weeks in transit.
More deaths in Juno Therapeutics’ CAR-T trial
Earlier this year, Juno Therapeutics’ CAR-T trial was paused as three patients died due to cerebral edema, in which fluids flood the brain. It was thought to be caused by the preconditioning regime with the chemotherapy fludarabine. Despite dropping the fludarabine, two new deaths due to cerebral edema occurred in this trial recently. Now, Juno faces tough questions about the safety of its therapy JCAR015. The FDA is likely to be vigorously questioned as well on the fact that they allowed Juno to proceed just days after the first clinical hold. Juno’s shares fell 44% before trading on it was halted; CEO Hans Bishop sold nearly $6 million worth of the company’s stock between its two clinical holds. CAR-T therapies are among the promising immuno-oncology treatments currently in clinical trials, although known for toxic symptoms such as cytokine release syndrome.
Celldex acquires Kolltan for $235M
Celldex Pharmaceuticals has completed its acquisition of Kolltan Pharmaceuticals for up to $235 million this November 29th. Kolltan is a private company focused on the discovery and development of novel antibody-based drugs that target receptor tyrosine kinases (RTKs). This deal is to expand Celldex’s antibody and immune-oncology portfolio with seven drug candidates under study in a range of difficult-to-treat oncology indications. Two of these include monoclonal antibody (MAbs) targeting KIT and ErbB3 (HER3), respectively, as well as a multi-faceted TAM program to generate antibodies modulating the TAM family of RTKs, comprised of Tyro3, AXL and MerTK. The Nasdaq listed company believes the expanded pipeline will allow for novel combination treatments, several of which are already in clinical trials.
EMA / FDA
The Committee for Medicinal Products for Human Use (CHMP) adopted a positive opinion for:
- Olaratumab (Latruvo, Eli Lilly) for the treatment of advanced soft tissue sarcoma (STS). Latruvo was designated as an orphan medicine in February 2015. The monoclonal antibody targeting platelet-derived growth factor (PDGF) receptor-alpha is used together with the anthracycline doxorubicin in patients who can’t undergo surgery or radiotherapy and who have not been previously treated with doxorubicin. Last month, olaratumab was approved by the FDA.
The FDA extended the indication of:
- Nivolumab (Opdivo, Bristol-Myers Squibb) for the treatment of recurrent metastatic squamous cell carcinoma of the head and neck (SCCHN). The anti-PD-1 antibody was already approved for other indications like Hodgkin’s lymphoma (HL), melanoma and non-small cell lung cancer (NSCLC). Approval was based on the results obtained in the randomized CheckMate 141 trial, in which the estimated Overall Survival (OS) was 7.5 months in the nivolumab group compared to 5.1 months for the investigator’s choice of chemotherapy.
- Daratumumab (Darzalex, Janssen Biotech), in combination with lenalidomide and dexamethasone, or bortezomib and dexamethasone, for the treatment of patients with Multiple Myeloma who have received at least one prior therapy. The monoclonal antibody that binds with high affinity to CD38 was granted accelerated approval as a monotherapy in November 2015. The current approval is based on 2 randomized trials; in neither of these trials PFS was reached when patients received a combination of daratumumab with lenalidomide and dexamethasone, thereby representing a 63% and 61% reduction in the risk of disease progression or death in patients.