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New Study from UCSD Shows That Chromosome Shattering Can Promote Cancer Cell Growth and Increase Resistance to Chemotherapeutic Drugs

The researchers also found that certain molecules, when added to cancer drugs, can prevent chromosome shattering from occurring in a discovery that may be useful to pathologists and oncologists

Anatomic pathologists who diagnose tissue and closely monitor advances in cancer diagnostics and therapy will be interested in a recent study into how a mutational process known as chromothripsis (chromosome shattering) can promote cancer cell growth in humans and increase resistance to cancer drug therapies.

The study, which was published in the journal Nature, titled, “Chromothripsis Drives the Evolution of Gene Amplification in Cancer,” provides insights into how cancer cells can adapt to different environments and also may suggest potential solutions to drug resistance among cancer patients. 

Led by researchers from the University of California San Diego School of Medicine and the UC San Diego branch of the Ludwig Institute for Cancer Research, the discovery could open up a new field in cancer diagnostic testing, where the pathology laboratory analyzes a cancer patient’s tumor cells to determine where chromosomal damage exists. This knowledge could then inform efforts to repair damaged chromosomes or to identify which therapeutic drugs would be most effective in treating the patient, a key element of precision medicine

Ofer Shoshani, PhD postdoctoral fellow at the Cleveland Lab at UC San Diego School of Medicine
“Drug resistance is the most problematic part of cancer therapy. If not for drug resistance, many cancer patients would survive,” said Ofer Shoshani, PhD (above right) postdoctoral fellow at the Cleveland Lab at UC San Diego School of Medicine and the study’s first author, in a news release. He’s shown with Don Cleveland, PhD (above left), head of the Cleveland Laboratory of Cell Biology at the Ludwig Institute for Cancer Research, another author of the study. Cleveland is also Chair of the Department of Cellular and Molecular Medicine, and Distinguished Professor of Cellular and Molecular Medicine, Medicine, and Neurosciences at UC San Diego School of Medicine. (Photo copyright: Ludwig Institute for Cancer Research.)

Shattered Chromosomes

Chromosomes that undergo chromothripsis shatter or fragment into several pieces and then are stitched back together by a DNA repair processes. However, not all of the fragments make it back into the repaired chromosome, and this can be a problem.

“During chromothripsis, a chromosome in a cell is shattered into many pieces, hundreds in some cases, followed by reassembly in a shuffled order,” Shoshani told Genetic Engineering and Biotechnology News (GEN News). “Some pieces get lost while others persist as extra-chromosomal DNA (ecDNA). Some of these ecDNA elements promote cancer cell growth and form minute-sized chromosomes called double minutes.”

Studies have shown that up to half of all cancer cells contain cancer-promoting ecDNA chromosome fragments.

Some Cancer Drugs Could be Fueling Drug Resistance

To perform their study, the UC San Diego/Ludwig scientists sequenced entire genomes of cancer cells that had developed drug resistance. Their research revealed that chromothripsis prompts and drives the formation of ecDNA and that the process can also be induced by some chemotherapeutic drugs. The researchers also discovered that the particular type of damage these drugs may cause can provide an opening for ecDNA to reintegrate back into chromosomes. 

“We show that when we break a chromosome, these ecDNAs have a tendency to jump into the break and seal them, serving almost like a DNA glue,” Shoshani said in the news release. “Thus, some of the very drugs used to treat cancers might also be driving drug resistance by generating double-stranded DNA breaks.” 

Preventing DNA Shattering and Reducing Drug Resistance

The scientists also discovered that ecDNA formation could be halted by pairing certain cancer drugs with molecules that prevent DNA shattering from occurring in the first place, thus reducing drug resistance.

“This means that an approach in which we combine DNA repair inhibitors with drugs such as methotrexate or vemurafenib could potentially prevent the initiation of drug resistance in cancer patients and improve clinical outcomes,” Shoshani said.

“Our identifications of repetitive DNA shattering as a driver of anticancer drug resistance and of DNA repair pathways necessary for reassembling the shattered chromosomal pieces has enabled rational design of combination drug therapies to prevent development of drug resistance in cancer patients, thereby improving their outcome,” Don Cleveland, PhD, Head of the Cleveland Laboratory of Cell Biology at the Ludwig Institute for Cancer Research and one of the authors of the paper, told GEN News.

This research from the University of California San Diego School of Medicine and the UC San Diego branch of the Ludwig Institute for Cancer Research is the latest example of how scientists have gained useful insights into how human genomes operate. More research and clinical studies are needed to solidify the advantages of this study, but the preliminary results are promising and could lead to new cancer diagnostics and therapies.  

—JP Schlingman

Related Information:

Shattered Chromosomes Found to Promote Cancer Cell Growth

Ludwig Cancer Research Study Reveals how ecDNA Forms and Drives Cancer Drug Resistance

Chromothripsis Drives the Evolution of Gene Amplification in Cancer

Data from Basket Studies Help Anatomic Pathologists Better Understand Effectiveness of Oncology Drugs

Pathologists can be paid for their role in identifying and recruiting patients for basket studies and reporting results of medical laboratory tests

Anatomic pathologists who biopsy, report, and diagnosis cancer will benefit from a better understanding of basket studies and their application in developing cancer treatment therapies. Such studies can lead to more documentation of the effectiveness of various therapies for cancers with specific gene signatures

The US National Library of Clinical Medicine defines basket studies as “a new sort of clinical studies to identify patients with the same kind of mutations and treat them with the same drug, irrespective of their specific cancer type. In basket studies, depending on the mutation types, patients are classified into ‘baskets.’ Targeted therapies that block that mutation are then identified and assigned to baskets where patients are treated accordingly.”

Also known as basket or bucket trials, basket studies involve patients who have different cancers at a various sites, such as lung, breast, and prostate, but whom share a common genetic mutation, explained Ryan Chandanais, MS, CPhT, Emerging Therapeutics Analyst at Diplomat Pharmaceuticals, Flint, Mich., in an article he penned for Pharmacy Times titled, “Basket Studies: An Innovative Approach for Oncology Trials.”

The popularity of basket studies has increased in tandem with genomic medicine’s rise, stated an article in Cancer Therapy Advisor titled, “Wider Use of Basket Trials Could Hasten Development of Precision Therapies.”

“Historically, cancer clinical trials have been centered on the treatment of cancer based on the anatomic location in the body, like breast cancer or brain cancer or lung cancer. A basket study is a novel trial design that includes patients with a certain molecular aberration regardless of location or tissue of origin of cancer in the body. The genomic revolution in oncology has fueled these studies,” Vivek Subbiah, MD, Associate Professor and Medical Director, Clinical Center for Targeted Therapy ( Phase 1 trials program), at the University of Texas MD Anderson Cancer Center in Houston, told Cancer Therapy Advisor. (Photo copyright: MD Anderson Cancer Center.)

Basket Studies Get Results

During a basket study, researchers may find that a drug’s effectiveness at targeting “a genetic mutation at one site can also treat the same genetic mutation in cancer in another area of the body,” noted Pharmacy Times, which also pointed out basket studies are often starting points for larger oncology trials about drugs.

For example, it was a basket study which found that vemurafenib (marketed as Zelboraf), intended for treatment of V600E, a mutation of the BRAF gene, may also treat Erdheim-Chester disease (a rare blood disorder) in patients who have the BRAF V600 gene mutation, Pharmacy Times reported.

Additionally, the US Food and Drug Administration’s approval of the cancer drug Vitrakvi (larotrectinib), an oral TRK inhibitor, marked the first treatment to receive a “tumor-agnostic indication at time of initial FDA approval,” a Bayer news release stated. The drug’s efficacy, Pharmacy Times noted, was found in a “pivotal” basket study.

Basket Studies, a Master Protocol Trial Design

The basket study technique is an example of a master protocol trial design. The FDA defines a master protocol as “a protocol designed with multiple substudies, which may have different objectives and involves coordinated efforts to evaluate one or more investigational drugs in one or more disease subtypes within the overall trial structure. A master protocol may be used to conduct the trial(s) for exploratory purposes or to support a marketing application and can be structured to evaluate, in parallel, different drugs compared to their respective controls or to a single common control.”

Other master protocols include umbrella studies and platform studies, according to Cancer Therapy Advisor, which noted that each master protocol trial design has its own unique objectives:

  • Umbrella studies look at the effectiveness of multiple drugs on one type of cancer;
  • Platform trials investigate the effectiveness of multiple therapies on one disease on an ongoing basis; and
  • Basket studies focus on the effectiveness of one therapy on patients with different cancers based on a biomarker.

“In contrast to traditional trials designs, where a single drug is tested in a single disease population in one clinical trial, master protocols use a single infrastructure, trial design, and protocol to simultaneously evaluate multiple drugs and or disease populations in multiple substudies, allowing for efficient and accelerated drug development,” states the FDA draft guidance, “Master Protocols: Efficient Clinical Trial Design Strategies to Expedite Development of Oncology Drugs and Biologics.”

Final FDA guidance on master protocols design is expected early in 2020, an FDA spokesperson told Cancer Therapy Advisor.

While master protocol studies show promise, they generally have small sample sizes, noted researchers of a study published in the journal Trials. And some researchers have ethical concerns about basket studies.

Scientist at the Jagiellonian University Medical College in Krakow, Poland, published a study in BMC Medical Ethics, titled, “Umbrella and Basket Trials In Oncology: Ethical Challenges,” in which they cite their concerns with basket studies, which are related to scientific validity, risk-benefit ratio, and informed consent.

Nevertheless, basket studies appear to hold promise for precision medicine. Anatomic pathologists may want to follow some of them or find a way to get involved through identifying clinical laboratory tests and reporting the results.

—Donna Marie Pocius

Related Information:

Basket Studies: An Innovative Approach for Oncology Trials

Basket Studies: Redefining Clinical Trials in the Era of Genome-Driven Oncology

Wider Use of Basket Trials Could Hasten Development of Precision Therapies

FDA Approves Vitrakvi (larotrectinib), the First Ever TRK Inhibitor for Patients with Advanced Solid Tumors Harboring an NTRK Gene Fusion

FDA: Design Strategies to Expedite Development of Oncology Drugs and Biologics Guidance for Industry

Systematic Review of Basket Trials, Umbrella Trials, and Platform Trials: A Landscape Analysis of Master Protocols

Basket Trials for Intractable Cancer

Umbrella and Basket Trials in Oncology: Ethical Challenges

Master Protocols: Efficient Clinical Trial Design Strategies to Expedite Development of Oncology Drugs and Biologics

Roche Molecular Gains FDA Clearance for Its Companion Diagnostic Test for New Skin Cancer Drug

Clinical laboratory managers and pathologists can expect more companion diagnostics in responses to advances in molecular knowledge about various diseases

Recently, the Food and Drug Administration (FDA) cleared two products for market, one of which may be of particular interest to anatomic pathologists. The first product is a therapeutic drug for the treatment of late-stage skin cancer. The second product is a companion clinical laboratory test that will be used to identify skin cancer patients most likely to benefit from this new drug.

This development is attracting attention by experts watching the molecular diagnostics marketplace. That’s because both products were developed by the same company on a tight timeline and this process is likely to be much studied by other pharma companies and genetic test developers.

The company that developed the new drug and its companion diagnostic test is Roche Holdings AG (OTCQX: RHHBY). In its press release about the FDA’s decisions, the company simultaneously announced market clearance of the drug Zelboraf (vemurafenib) and the approval of the companion diagnostic, the cobas 4800 BRAF V600 Mutation Test.