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Friday, December 2, 2016

Researchers at Mayo Clinic Center for Individualized Medicine have discovered a potential cause and a promising new treatment for inflammatory myofibroblastic tumors, a rare soft tissue cancer that does not respond to radiation or chemotherapy.

New research from Aaron Mansfield, MD, an oncologist at Mayo Clinic, and George Vasmatzis, PhD, the Co-Director of the Biomarker Discovery Program of Mayo Clinic Center for Individualized Medicine, finds the drug ceritinib shows promise as a new treatment for inflammatory myofibroblastic tumors (Ann Oncol 2016;27(11):2111-17). The study also traced tumor growth to chromoplexy: a complex chromosomal rearrangement that causes genes to scramble, break DNA strands, and then reassemble in a defective way.

Investigators made the connection when a 32-year-old man failed to respond to a nonsteroidal anti-inflammatory drug to shrink tumors in his lung, chest, and buttock. Because there were no available clinical trials, researchers sought and gained FDA approval for compassionate use of ceritinib. Within 2 weeks, the patient started responding to the drug. After 18 months, he was well enough to undergo surgery to remove tumors from his lung and buttock. Mayo researchers were able to conduct a new DNA test on the tumors known as mate pair sequencing. They found 142 genes had been impacted, many of which have known links to cancerous tumors.

"Mate pair sequencing helped identify these rearrangements, which may not have been seen with normal sequencing techniques," noted Mansfield. "We look forward to offering more patients this new, advanced type of DNA testing to discover potential causes and treatments for diseases."

The main form of treatment for patients with an inflammatory myofibroblastic tumor is surgery, but the tumors often reappear in different parts of the body. There is no standard of care for patients with inflammatory myofibroblastic tumors, thus making the discovery of tumor response to ceritinib all the more important. Mayo Clinic investigators are recommending further study of this drug to determine whether it should be approved for individualized treatments.

Friday, December 2, 2016

Positive updated results from a pivotal phase III clinical trial evaluating aldoxorubicin compared to investigator's choice in patients with relapsed or refractory soft tissue sarcomas (STS) were recently released.  

The randomized, controlled phase III trial enrolled a total of 433 patients at 79 clinical sites. Patients with metastatic, locally advanced or unresectable soft tissue sarcomas who had either not responded to or who had progressed following treatment with one or more systemic regimens of non-adjuvant chemotherapy were randomized 1:1 to be treated with aldoxorubicin or the investigator's choice of an approved chemotherapeutic regimen, including doxorubicin, ifosfamide, dacarbazine, pazopanib, or gemcitabine plus docetaxel. The primary endpoint of the study is progression-free survival (PFS). Secondary endpoints include overall survival, response rates, disease control rates, and safety.

The study demonstrated a statistically significant improvement in PFS between aldoxorubicin and investigator's choice therapy in 246 patients with leiomyosarcoma and liposarcoma, (p=0.007). The hazard ratio (HR) was 0.62 (95% CI 0.44-0.88), representing a 38 percent reduction in the risk of tumor progression for patients receiving aldoxorubicin versus investigator's choice.

Aldoxorubicin demonstrated a statistically significant improvement in PFS over investigator's choice in 312 patients treated in North America (p=0.028; HR=0.71, 95% CI 0.53-0.97). Notably, aldoxorubicin performed better than investigator's choice for the entire study population and narrowly missed statistical significance (p=0.12; HR=0.81, 95% CI 0.64-1.06). All responses were determined by an independent, blinded central lab assessment of scans.

"This data represents a major step forward for STS, a rare, highly complex and very difficult-to-treat group of cancers," commented Sant Chawla, MD, FRACP, Director of the Sarcoma Oncology Center in Santa Monica, Calif., and principal investigator for the trial. "These results are important because they demonstrate that treatment with aldoxorubicin can extend the time to progression in a clinically meaningful way. The trial design used was more stringent than any prior clinical trial in STS as it compared aldoxorubicin to real world alternatives. The control arm allowed trial investigators to select any one of the five most widely used treatments best suited for their patients' specific type of STS. Unlike other clinical trials for relapsed or refractory STS which used either dacarbazine or placebo as the control, this study was biased in favor of choosing the best therapy for the patients, a truly unique study design."

In the entire study population, aldoxorubicin achieved a statistically significant improvement in the disease control rate (DCR; defined as objective response rate (ORR) plus stable disease for at least 4 months) of 29.4 percent versus 20.5 percent for the patients treated with investigator's choice (p=0.030). In North American patients, the benefit was even more pronounced with aldoxorubicin-treated patients exhibiting a DCR of 32.9 percent, compared to 19.2 percent for patients treated with investigator's choice (p=0.007), an overall improvement of 71 percent. ORR in North American patients also favored aldoxorubicin over investigator's choice, 8.7 percent versus 3.3 percent (p=0.058). Of note, no objective responses were observed in patients treated with pazopanib. Patients continue to be followed for overall survival (OS), a secondary endpoint, and OS data is expected to be available in 2017.

Pre-specified analyses were based on sarcoma histopathology and geography. The geographic analysis includes patients from North America (defined as the U.S., Canada, and Australia, per the trial statistical analysis plan). The 312 patients treated in North America comprise 72 percent of the total trial population, including 296 patients from the U.S., eight patients from Canada, and eight patients from Australia. The 246 patients with leiomyosarcoma or liposarcoma comprise 57 percent of the total trial population.

Aldoxorubicin did not cause clinically significant cardiac, renal, or hepatic toxicities. For the global trial population, the most commonly reported adverse events were neutropenia and anemia consistent with prior clinical trials with aldoxorubicin. Grade 3 or higher hypertension occurred in patients receiving pazopanib.  Grade 3 or higher adverse events were manageable with supportive care and occurred at a rate of 61 percent for patients receiving aldoxorubicin and 46 percent in patients treated with investigator's choice. Importantly, treatment-emergent adverse events leading to discontinuation occurred in 4.2 percent of patients treated with aldoxorubicin, compared to 6.3 percent for patients receiving investigator's choice. Serious adverse events, primarily febrile neutropenia that resolved and rarely led to treatment termination occurred more frequently in patients administered aldoxorubicin. Treatment-related deaths occurred in one aldoxorubicin-treated patient and in no patients receiving investigators' choice drugs.

Friday, December 2, 2016

A common cell signaling pathway that controls differentiation of stem cells may also control the formation of tumor cells in fat, according to a Purdue University study.

This signaling pathway, called Notch signaling, has been widely reported to determine the identity and control the differentiation of a variety of stem cells in different tissues. Notch signaling occurs between two neighboring cells, in which one cell sends a signal to the neighbor cell to control its gene transcription program that determines the identity of the neighbor cell.

Shihuan Kuang, PhD, Professor of Animal Sciences at Purdue, had earlier determined that when Notch signaling is suppressed, white fat cells, which are linked to obesity due to their ability to accumulate excessive lipids, turn into beige fat cells. Beige fat is more metabolically active and breaks down lipids by turning them into heat.

It's possible that humans evolved to build up white fat, which acted as insulation but also as an energy store and endocrine organ. The physical activity required to live off the land would have kept white fat from over accumulating in most people. As we have become less active, however, energy stored in white fat is not spent and its over-accumulation is associated with metabolic diseases such as diabetes, obesity, and some types of cancer.

"Beige fat, if you consider human physiology, is wasting energy," said Pengpeng Bi, PhD, a former Purdue postdoctoral fellow and lead author. "But it would be good for us now because we are overfed and more inactive."

Researchers wanted to know what would happen if Notch signaling is overactive in fat cells. The findings, published in the Journal of Experimental Medicine, show that when Notch signaling is turned up beyond normal levels in mice, those same white fat cells degenerate and turn cancerous (DOI: 10.1084/jem.20160157).

"A normal amplitude of Notch signaling is required for a human or animal to develop, but overactive Notch signaling is linked to cancer in several cell types," Kuang said. "Our study demonstrates for the first time that Notch activation is sufficient to drive the development of malignant tumors in fat tissue, termed liposarcoma."

Tumors of this kind aren't common, but Kuang said that liposarcomas can be devastating and hard to treat, mainly because surgical excision, the standard treatment, often leads to uncontrolled recurrence that causes death. This new study suggests that pharmacological inhibition of Notch signaling may be effective in treating a subtype of liposarcomas in humans.

Understanding how overactive Notch signaling shrinks fats cells and turns them into cancerous cells is the emphasis of Kuang's future work. "We hope the study could give clues on the development and treatment of metabolic diseases including obesity, type 2 diabetes, lipodystrophy, and liposarcomas," Kuang concluded.

Thursday, December 1, 2016

An optical fiber probe can distinguish cancer tissue and normal tissue at the margins of a tumor being excised, in real time, by detecting the difference in pH between the two types of tissue. This has the potential to help surgeons avoid removing too much healthy tissue during surgery and also avoid performing additional surgeries later to remove any cancer tissue left behind, according to a study published in Cancer Research (DOI: 10.1158/0008-5472.CAN-16-1285).

"We have designed and tested a fiber-tip pH probe that has very high sensitivity for differentiating between healthy and cancerous tissue with an extremely simple experimental setup that can already be used in a fully portable configuration," said Erik P. Schartner, PhD, a postdoctoral researcher at the School of Physical Sciences and the ARC Centre of Excellence for Nanoscale BioPhotonics (CNBP)  at The University of Adelaide in Australia, working in collaboration with the Breast, Endocrine & Surgical Oncology Unit at the Royal Adelaide Hospital.

"Because it is cost-effective to do measurements in this manner compared to many other medical technologies, we see a clear scope for broader use of this technology in operating theaters," he added.

A major issue with current surgical techniques to resect cancer is the lack of a reliable method to identify the tissue type during surgery; therefore the surgical procedures rely extensively on the experience and judgement of the surgeon to decide on how much tissue to remove around the tumor margins, Schartner said. Because of this, surgeons often perform what is called cavity shaving, which can result in the removal of excessive healthy tissue. On the other hand, many patients do not have the entire tumor removed during the initial surgery, and will need a follow-up surgery to remove residual cancer tissue.

"This is quite traumatic to the patient, and has been shown to have long-term detrimental effects on the patient's outcome," Schartner stated.

Schartner and team designed an optical fiber probe that can detect cancer cells during surgery based on the principle that cancer and normal cells have different pH, which is a measure of the acidity or basicity (alkalinity) of a substance. Tumor cells are typically more acidic than normal cells, Schartner noted.

When the probe is applied to the tissue, the pH indicator embedded in the polymer layer at the tip of the fiber optic probe changes the color of the light it emits depending on the pH of the area that it is placed in. The probe is connected to a light source, which emits fluorescence that can be detected with a miniature spectrometer on the other end of the probe, Schartner explained.

The researchers tested their probe on four mastectomy specimens, one specimen of axillary clearance from a patient with recurrent breast cancer, and three specimens of metastatic melanoma. After multiple measurements of the margins of these samples, the researchers found that this pH method was able to differentiate tumor and normal areas with 88 percent sensitivity and 90 percent selectivity. Pathological evaluation of these samples to determine tumor and normal areas was used as reference.

In order to avoid interference in measurements from autofluorescence, the researchers employed a "lift and measure" technique. To do this, the probe is first made to touch the tissue, but the fluorescence is measured after the probe is lifted from the tissue surface, at which point the probe retains the initial measurement but is devoid of the interference from the light emitted by the tissue.

"Eliminating the autofluorescence background by the 'lift and measure' method we used overcomes one of the main limitations that usually restricts the performance of fluorescence-sensing methods," Schartner noted. With their probe, the initial signal was stable up to 10 minutes after lifting.


"We are currently in the process of obtaining more excised tissue samples to increase our database, with the view of moving this towards clinical studies in the near future," Schartner said. "We are pushing strongly for commercial development of this probe with industry partners."

Limitations of the study include the small sample size and further improvements needed to enhance the probe's specificity.

Tuesday, November 29, 2016

In a new study, a group of Boston scientists offer a genetic explanation for the age-old conundrum of why cancer is more common in males than females.

Females carry an extra copy of certain protective genes in their cells -- an additional line of defense against the cells growing out of control -- the investigators report in a paper published online by Nature Genetics (DOI: 10.1038/ng.3726). Though not solely responsible for cancer's "bias" toward males, the duplicate copies likely account for some of the imbalance, including up to 80 percent of the excess male cases in some tumor types, report the study authors, based at Dana-Farber, the Broad Institute of Harvard and MIT, and Massachusetts General Hospital.

"Across virtually every type of cancer, occurrence rates are higher in males than in females. In some cases, the difference might be very small -- just a few percent -- but in certain cancers, incidence is two or three times higher in males," said Andrew Lane, MD, PhD, of Dana-Farber, the co-senior author of the study with Gad Getz, PhD, of the Broad Institute and Massachusetts General Hospital. "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."

Despite the size of the gap, the reasons for this divergence have been difficult to discern. The historic explanation -- that men were more likely to smoke cigarettes and be exposed to hazardous chemicals in the work environment -- has proven inadequate, because even as smoking rates have dropped and occupational patterns changed, men still outpace women in developing many cancers, including some associated with tobacco use such as kidney, renal, bladder, and oral cancers, Lane said. The disparity is present among boys and girls, as well as men and women.

Previous research found that in one form of leukemia, the cancer cells often carried a mutation in a gene called KDM6A, located on the X chromosome -- one of the sex chromosomes that determine whether an individual is male or female. If KDM6A is a tumor-suppressor gene -- responsible for preventing cell division from spinning out of control -- the mutation could lead to cancer by crippling that restraint system.

One might expect female cells to be just as vulnerable to the mutation. During embryo formation, one of the X chromosomes in female cells shuts down and remains off-line for life. A mutation in KDM6A on the active X chromosome, therefore, should lead to the same cell-division havoc as it does in males. Unexpectedly, KDM6A mutations were detected more often in male cancers. It turns out that some genes on the inactivated X chromosome in female cells "escape" that dormant state and function normally. One of those awakened genes happens to be a working copy of KDM6A. The "good" copy of the gene is sufficient to prevent the cell from turning cancerous.

The new study explored whether this phenomenon -- fully functional tumor-suppressor genes on an otherwise idle X chromosome -- underlies the broader phenomenon of cancer's partiality toward male cells. The researchers dubbed such genes "EXITS," for Escape from X-Inactivation Tumor Suppressors.

"Under this theory, one of the reasons cancer is more common in males is that male cells would need a harmful mutation in only one copy of an EXITS gene to turn cancerous," Lane said. "Female cells, by contrast, would need mutations in both copies."

To test this hypothesis, researchers at the Broad Institute scanned the genomes of more than 4,000 tumor samples, representing 21 different types of cancer, looking for various types of abnormalities, including mutations. They then examined whether any of the irregularities they found were more common in male cells or female cells.

Of nearly 800 genes found solely on the X chromosome, six were more frequently mutated -- and incapacitated -- in males than females. Of more than 18,000 other genes, none showed a gender imbalance in mutation rates. Of the six genes more likely to be mutated in males, five were known to escape X chromosome inactivation, making them strong candidates to be EXITS genes.

"The fact that the very genes which are more often mutated in males are found exclusively on the X chromosome -- and that several of them are known to be tumor-suppressors and escape X-inactivation -- is compelling evidence of our theory," Lane remarked. "The protection afforded by the working copies of these genes in female cells may help explain the lower incidence of many cancers in women and girls."

One of the implications of the finding is that many cancers may arise through different molecular pathways in men and women. To circumvent the added genetic safeguards against cancer in female cells, tumors in women may employ alternate genetic circuits than in men.

To explore this possibility, the study authors recommend that future clinical studies of cancer treatments be "statistically powered" ¬- that is, involve enough patients and tumor tissue samples -- to understand whether men and women respond differently to treatment because of genetic differences in their tumors.​

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