In-Depth Analysis of Metastatic Cancer Could Enable More Precise Treatments

Five hundred cancer patients are getting an in-depth look at their genomes as part of a new clinical study that is revealing some of the key molecular drivers of metastatic cancers. Some of the patients, who were diagnosed with more than 20 different types of cancer among them, are now working with their physicians to use their genomic information to guide treatment options.

The data are helping physicians match patients to clinical trials that address the precise DNA mutations that enable their cancers’ growth, says study coauthor Arul Chinnaiyan, an HHMI investigator and cancer biologist at the University of Michigan. He is among the first researchers to take this kind of precision medicine approach to better understand and treat metastatic cancers – an aggressive form of the disease in which cells from the original tumor break away and invade other tissues.

Chinnaiyan’s findings, published August 2 in the journal Nature, contribute to a growing body of research that reveals the molecular underpinnings of patients’ tumors. Chinnaiyan’s team has also made their dataset available to other scientists investigating metastatic cancer.

“Ninety percent of the time, metastatic cancer is the form of cancer that patients die of,” Chinnaiyan says. “It’s very difficult to treat once you have it.”

Caption: Arul Chinnaiyan’s team analyzed a variety of metastatic cancers throughout the body, including lung cancer (green) and breast cancer (pink). Credit: Alexander Tokarev

The ongoing clinical study employs tumor sequencing, in which researchers extract tumor cells from patients and characterize the cells’ genetic makeup. Using this information, Chinnaiyan and his team can create molecular profiles of the tumor that reveal details of what went awry – such as mutations, gene fusions (when two separate genes erroneously combine) and other molecular abnormalities. The data pointed Chinnaiyan and his team to five genes, all of which were commonly altered in patients with metastatic cancer. Additionally, the researchers observed that 12 percent of patients carried potential cancer-causing errors in DNA carried by sperm and egg cells.

“This gave us a pretty comprehensive picture of the molecular landscape of cancer,” said Chinnaiyan.

The data are a result of two genomic sequencing techniques – DNA and RNA sequencing, or whole-exome and transcriptome sequencing, respectively. In DNA sequencing, researchers extract and analyze DNA from a patient’s tumor and healthy tissues to try and discern what went wrong in the tumor. By comparing the two sets of DNA sequences, scientists can pick out genomic differences between the normal and the tumor DNA. “That's key because it allows us to potentially know what's driving the cancer in that individual patient,” Chinnaiyan said.

RNA sequencing allows researchers to better identify deleterious alterations, such as gene fusions or changes in gene expression. Chinnaiyan and his team also used RNA sequencing to analyze the amount and type of immune cells that infiltrated the patients’ tumor-invaded tissues. RNA sequencing data, he says, allows a clearer glimpse into the “immune phenotypes” associated with individual cancers – in other words, the factors that suppress the immune system’s ability to fight tumor growth.

“Immunotherapy has been one of the major areas of progress in cancer therapeutics, thus emphasizing the need to understand the immune microenvironment of the tumor,” Chinnaiyan explains.

He says that it’s crucial to understand that cancer is never static and always evolving – and treatments should reflect that. As tumors cross into different tissues, new mutations may arise, changing their molecular composition, which could diminish the efficacy of cancer drugs. Likewise, tumors can adapt to therapeutic drugs and develop new ways to survive. To maintain the most effective, up-to-date, treatment, Chinnaiyan argues that more frequent biopsies (of both the tumor and its immune microenvironment) are critical.

“We should be doing contemporaneous sequencing of cancer patients’ genomes – real-time assessments of the patient rather than relying on recommendations based on archival samples of the primary tumor,” he says.

Now, Chinnaiyan and his team are continuing to gather sequence data from patients with metastatic cancer. The researchers want to build and contribute to a large database for scientists and doctors to use. Chinnaiyan hopes that a genome-first approach will help doctors and patients develop agile treatment strategies that remain effective despite the dynamism of metastatic cancer.

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Dan R. Robinson et al. “Integrative clinical genomics of metastatic cancer,” Nature. Published online August 2, 2017, doi: 10.1038/nature23306.

Lessons from the Tarantula

Picture an organism the size of your hand, with a bristly body and eight bushy legs. Chances are, you’re thinking of a tarantula. As familiar as these shaggy arachnids are, it may surprise you to learn that they harbor a secret about human health: the muscles that control each spindly limb bear a remarkable molecular resemblance to the muscle beating in our chests.

For Christine Seidman, a human molecular geneticist and HHMI investigator at Brigham and Women’s Hospital and Harvard Medical School, that likeness gave her a new perspective on heart disease. Seidman studies a heart disease called hypertrophic cardiomyopathy (HCM). For those with HCM, the heart contracts too well, and does not relax properly, which increases energy consumption and leads to adverse events such as arrhythmias and heart failure.

Seidman’s past work has identified eight genes encoding for muscle proteins that, if mutated, cause HCM. Most commonly these mutations occur in two of the genes, one of which codes for myosin, a protein crucial to muscle contraction. The myosin-related mutations simply switch one amino acid for another during the protein-building process. These findings prompted a new question: “How could such a subtle change have such profound effects?” In search of an answer, Seidman looked beyond genetics.

During an HHMI science meeting in 2011, Seidman sought help from Raúl Padrón, a structural biologist at the Venezuelan Institute for Scientific Research (I.V.I.C.), whose journal articles she’d been following. At the time, Padrón was an HHMI international research scholar studying how muscle proteins interact in tarantulas (which he describes as “very friendly”).

“One of the critical proteins that Raúl was studying was – big surprise – myosin,” said Seidman.

Armed with the title of Padrón’s poster at the HHMI meeting, she set out to find him. Padrón recalls their first interaction in vivid detail: “I was in complete shock when Christine came to my poster; I had never met her before, and she was very well-known in my field, as she discovered many of the mutations we were mapping in the myosin model in our poster. She walked up to me and said ‘We need to work together to understand how different mutations affect the myosin motif.’”

And so, they did. Padron paired his expertise in structural biology with Seidman’s keen knowledge of genetics. Together with collaborators Lorenzo Alamo and Antonio Pinto, they investigated how HCM-associated mutations change the structural interactions of myosin that occur during cardiac relaxation.

As a geneticist, Seidman says it was beautiful to see the actual myosin structure, even at low resolution. “And there was another piece that was very important to me – Raúl could tell me the amino acids that participate in myosin interactions during relaxation.” It turned out that many of the amino acids involved in the molecular interactions that occur with relaxation are the very ones that are altered by HCM mutations. That, she said, was “an a-ha moment.”

Baby Venezuelan tarantula. Image credit: Raúl Padrón

Now, the two are planning next steps, asking the natural follow-up questions in their respective fields.

“We hope to take advantage of the ongoing ‘cryo-EM resolution revolution’ to achieve near-atomic resolution of myosin interactions by using this technique, which was actually invented by Humberto Fernández-Morán, a Venezuelan scientist working at Chicago University in 1966,” Padrón says. Seidman, too, hopes to continue structural analyses. “We’d very much like to work with Raúl to solve these structures using human specimens, with and without HCM mutations,” she says. “That would be a big step."

But the clinician side of Seidman hopes the information will help them answer a different question.

“We also want to know if there is a way to reduce the symptoms and adverse outcome that occur in HCM, by improving relaxation, with small molecules in the heart. In addition, we know that abnormal relaxation of the heart occurs in a lot of different diseases, not just HCM, so understanding if these structures might contribute to broader cardiovascular disease will also be very, very important.”