Families Can’t Wait

Families Can’t Wait

Lynda Carter Altman helping fund and advocate for blood cancer research

On television, Lynda Carter Altman played Wonder Woman, a resilient, resourceful superhero. Through the iconic role, her likeness became synonymous with strength. Throughout the years, her representation has endured as a celebrated symbol of these characteristics. 

In real life, she isn’t all that different from her legendary on-screen persona. 

When Robert, her husband of 37 years, became ill with myelofibrosis—a malfunction of cells in the bone marrow—Carter Altman was every bit as resilient, resourceful, and strong. She threw herself into understanding the disorder, what treatment options were available, and what lay ahead. 

TGen and City of Hope were there to help.  

Tragically, Altman passed away last year when his myelofibrosis transformed into secondary acute myeloid leukemia (sAML), a rare blood cancer with limited treatment options. As his caregiver, Carter Altman experienced first-hand the unique challenges associated with treating and managing a rare cancer and the need for improved timely diagnosis and treatment. 

In September, she provided a philanthropic gift to accelerate critical research at TGen and City of Hope (COH) aimed at helping patients and families experiencing diagnosis and treatment challenges of this blood disorder.

A Book with Two Pages

Because people often show no symptoms in the early stages of myelofibrosis, doctors initially monitor the disease. Essentially, you wait. Watch to see what happens. Test again in a few months. And so on. 

When the disease eventually advances to sAML, it’s often a case of too little, too late, given existing treatment options and the medical field’s relatively limited knowledge of the mechanisms that lead to disease transformation.

“It just doesn’t make any sense to me that you watch it until it’s going to kill you,” Carter Altman says bluntly. “Then you hurry up and do something. It doesn’t make any sense to me to approach a disease, this kind of potential cancer, and then you’re just going to watch it until it turns deadly.”

To complicate matters further, Robert got sick during the COVID lockdowns. “Not being able visit the doctor in person was very frustrating,” Carter Altman elaborates. “So, I’m calling Dr. Trent to get answers.”

Jeffrey Trent, Ph.D., President and Research Director at TGen, and Carter Altman are lifelong friends, having known each other since grade school. He’s an internationally-renowned scientist in the field of genomics, particularly the field of translational genetics that applies genomic information for physician treatment decision support. 

“I called him about Robert. And he was so patient, explaining so much of it to me; and that’s what I needed. Information. Understanding. You know, an answer to ‘what is going on here?’”

Now, Carter Altman’s quest for answers has transitioned to helping other families in the same situation.

“It’s basically a book with two pages,” Trent says, displaying a gift for explaining complex science in accessible terms, “The first page, it’s all focused on early detection, early detection, early detection.”

Despite advances in medical research, patients and their families still lack information and options to identify the problem early, detect critical transition points of the disease, and target these transition points for a cure. Early detection of disease progression—identifying the critical transition point when myelofibrosis has advanced to the deadly sAML—is critical to finding effective treatments. 

Using ultra-rapid, whole genome sequencing, TGen researchers hope to reduce the window for returning results to clinical teams from two weeks to two days. 

That two-day turnaround can provide much-needed answers much faster for a patient and their loved ones, regardless of what comes next.  As Carter Altman put it, “I just want the truth, and I want it in real-time. We want a cure, of course, but in the meantime, we want to improve the quality of life and keep it from moving on to the next stage.” For the medical teams treating patients, early detection provides a larger window for intervention.

“The second page is on therapy to prevent and eventually cure sAML,” Trent continues.  

The overarching goal of this program is to develop new genetic tests and initiate clinical trials with new drugs designed based on the novel discoveries from these new genetic tests. The physician-scientists at COH are leaders in developing next-generation cancer therapies and rapidly deploying them for patient benefit. 

Beyond a Needle-in-a-Haystack

Early detection is often described as a “needle-in-a-haystack” problem. You are trying to pinpoint when myelofibrosis transforms into sAML—or, rather, when the blood disorder becomes deadly—and COH physicians and scientists have shown that by measuring when cells have begun losing a specific gene (miR-142) the disease may be accelerating. Having an “early detection” signal can help patients like Robert who are told to just “wait” and “monitor.” Currently doctors send blood from the patient with myelofibrosis off to the lab to test every couple of months, sometimes over years, to see when the disorder becomes a cause for concern—but by the time it does, they are in a desperate race against time without life-saving solutions for the onset of sAML. 

If you can observe these cells at the earliest possible moment when they are very rare, you have a much less complicated disease and a wider window to intervene. Earliest detection comes down to identifying such cells when they are 1:100,000 to 1:1,000,000. 

“Needle-in-a-haystack doesn’t quite cut it,” Trent observes. “Remember, if we look at somebody’s genome, we’re looking at billions of data points, sequenced hundreds of times, so it’s easily hundreds of billions of data points … and that’s a lot of information.” 

Instead, Trent says, better to imagine the Webb Telescope peering from galaxy to galaxy in search of a single star at a single point in time. Lots of data to sort through to find the gene mutation or mutations that cause this disorder.

“It turns out physics equations can be adapted and can provide a very effective tool to predict when cells in the body evolve from good to bad,” says Guido Marcucci, M.D., a physician-scientist of COH with world expertise in AML. “We can utilize mathematical modeling to look at the evolution of the disease and predict how and when it is going to transform into sAML.”  

Marcucci was born in Rome, Italy, but moved to the U.S. in 1990. He trained at Roswell Park Cancer Institute in Dr. Caligiuri’s laboratory and then joined him in a move to The Ohio State University (OSU) Comprehensive Cancer Center to work as a physician-scientist in 1997. In 2015, he became Director of the Gehr Family Center for Leukemia Research and as Chief of the Division of Hematopoietic Stem Cell and Leukemia Research at City of Hope. Dr. Caligiuri is the former Director of OSU’s Cancer Center and CEO of OSU’s James Cancer Hospital.  He rejoined Dr. Marcucci at COH in 2018 when he became President of City of Hope’s National Medical Center.  “Our lives have been intertwined around AML for 30 years,” says Caligiuri, “and I’ve gone from mentor to student”.

New methods of analyzing individual cells allow scientists to measure molecules like miR-142  and other gene changes even when the events are very rare. This enhances the ability to identify the disease early. Using a series of samples collected over time from the same patients spanning the period they transitioned from myelofibrosis to sAML can begin to document this evolution. 

“We generate incredible amounts of information,” Marcucci continues, “Collaborating with mathematicians as a part of our diagnostic team to create mathematical modeling increases our accuracy on knowing when and how the disease will evolve.” 

This is the bench to bedside back to the bench in action. 

“It’s actually these mathematicians that do an extraordinary job of refining our search. While there’s an incredibly important laboratory component—you get to generate all the data— I give real credit to the fact that we can do some things now with mathematics applied to the wealth of genomic data that are extraordinary,” Trent adds.

Therapy – Finding A Silver Bullet 

Caligiuri always wanted to be a physician. His specialization at the intersection of immunology and cancer resulted from a chance occurrence with a patient.

“I had an experience in medical school,” he explains. “A patient was rejecting his transplanted kidney. He couldn’t make urine. It was serious. I was allowed to give him an experimental drug that reversed the rejection and allowed the kidney to make urine. It was amazing.” 

For Caligiuri, the right drug at the right time for the right patient was inspiring. 

“At that moment, I said I want to be in transplant immunology,” he reflects. “I went into a lab to focus on curing leukemia with immune therapy. This was a perfect intersection.” 

Today, he is recognized as a leading researcher in immunology, lymphoma, and leukemia. At City of Hope, he dedicates himself to developing the next generation of cancer therapies. 

While TGen, led by Trent, develops the ultra-rapid genome sequencing, COH focuses on therapeutic avenues targeted to the cells that drive the transition to sAML. Most promising is a systematic, pre-clinical battery of tests necessary to advance the miR-142 drug, CpG-M-142, that could replace the action of a missing signal in defective cancer cells. The human clinical trial that is planned could add years to a patient’s life.

“Myelofibrosis is basically the result of one cell misbehaving because of one or a few mutated genes that in turn wreak havoc on neighboring cells causing more genes to mutate until the disease evolves to fatal sAML,” Caligiuri explains, “We want to keep that from happening—basically returning normal gene function to the cells before the process gets out of control—allowing the patient to stay alive and not develop sAML.”

“We are looking for a silver bullet. CpG-M-142 is able to correct the lack of miR-142 and to prevent transformation or in some cases successfully treat disease that has already transformed. We have seen outstanding results in the preclinical testing of the drug with very little toxicity” Marcucci enthuses. 

“Without Lynda’s generous donation, our progress would remain incremental and take many years to move into the clinic. Her support allows us to move toward human trials in a very short amount of time—not ten years, not five years—but within the next 3 years. It accelerates what we can accomplish.” 

And that acceleration potentially translates to lives saved and families spared. 

Looking to the Future

“The cure for cancer is going to come by preventing it,” Caligiuri states, “utilizing  genomic sequencing in normal individuals will someday soon identify those likely to develop cancer and precision therapeutics will prevent it from happening altogether.” 

It is a wild concept to imagine: being able to know what cancers you will likely develop and begin prevention therapy before it emerges. 

Marcucci’s distinguished career has been based on the belief that AML is the “prototype of cancer and how cancer develops,” which means this research may ultimately extend beyond the trials and treatments developed now.

As the financial cost of genomic technology falls, deployment of data-intensive, whole genome testing will inevitably become the standard of care. As this approach enters the mainstream, the companion challenge will be to deploy the tests early and rapidly. This will require increased efficiencies at every step of the process. 

This work supported by Lynda Carter Altman will provide a comprehensive demonstration of how to achieve the genomics-based care for all cancer patients in the future.

“Rapid genome testing is really something remarkable,” Carter Altman says, “If we can get those tests down to 2 days and do it in a way that is more cost-effective and more accessible, well, you can have an earlier diagnosis. The earlier the diagnosis, the earlier you can treat it. The earlier you can treat it, the better your chances of survival.”

That is a remarkable legacy for any family to leave. 

(TGen home page slider image photo courtesy of Nathan Congleton)