It’s the Metastases, Stupid: Tackling Primary and Metastatic Bone Cancer at “Pitt”

by Elizabeth Hofheinz, M.P.H., M.Ed., December 4, 2019

There is the, “hmmm, I wonder” type of curiosity…and then there is the, “I have to know” type of curiosity. It was the latter that sent a young Kurt Weiss, now an M.D. and associate professor of orthopaedic surgery in the Division of Musculoskeletal Oncology at the University of Pittsburgh Medical Center, straight to medical school.

Why? Because Kurt Weiss was diagnosed with metastatic osteosarcoma at the age of 15.

“The primary tumor was in my right tibia and it had metastasized by the time of my diagnosis,” he told OSN. “I underwent chemotherapy then surgery to remove the tumors in my leg and lungs. While on chemo the disease returned to the lungs, which indicated that the chemo was not working. Things went so far that my parents actually purchased a burial plot for me.”

“Not today,” said destiny.

Dr. Weiss: “During this time my sister read an article in the newspaper about a clinical trial for children who had been diagnosed with osteosarcoma that had gone to the lungs. I enrolled and the craziest thing happened…it worked!”

Now Dr. Weiss is co-director of the Musculoskeletal Oncology Laboratory at “Pitt,” a facility whose mission is to better understand the biology of primary and metastatic musculoskeletal tumors. The group works to investigate novel pharmacological and molecular approaches to target metastatic sarcoma and breast cancer bone metastases. The main focus is maintaining a vigorous and comprehensive research program for musculoskeletal oncology at the University of Pittsburgh with the goal of translating discoveries into clinical solutions for patients. The group has initiated and maintains a musculoskeletal oncology tumor registry and tissue bank. This unique resource enables the team to perform truly innovative and translational research that combines the strengths of the clinical volume of the UPMC Hillman Cancer Institute with the research infrastructure at the University of Pittsburgh. These patient clinical data and tissue samples provide a powerful research resource that is not attainable elsewhere.

Dr. Weiss: “At that time, immune therapy was very rudimentary, but these days it is a hot topic. The fundamental idea is to increase immune surveillance in the lungs. And while I am not an immunologist, I know metastatic cancer and I know that while we can eliminate tumors in the arm or leg, when cancer goes to the lungs we have no way to address that.”

Detailing their work is Rebecca Watters, Ph.D., co-director of the Musculoskeletal Oncology Laboratory and the Pittsburgh Center for Bone & Mineral Research. “Of all patients with breast cancer, 30% develop metastases; of those, three out of four are in bone. I became interested in how the gene expression in the metastases differs from that in the primary tumor.

However, the vast majority of all the research funding is funneled to primary breast cancer and early detection and prevention. Thus, there are a lot of individuals living with metastatic cancer are essentially given a death sentence.”

“What about the rest of us?”

“Our best estimate is that there are 155,000 patients in the U.S. who have metastatic cancer; according to Metastatic Breast Cancer Alliance those numbers are higher. Fortunately, these individuals have banded together and have begun advocating for themselves. They are saying, ‘What about the rest of us?’”

“One of the interesting—and sad—things that I learned from the metastatic patients who sought out support groups is that some people are turned away because the leader is worried that they will frighten the newly diagnosed people.”

But there is progress, albeit slow.

“A few years ago, only 2% of all breast cancer funding is directed to metastatic breast cancer; now it has increased just a bit to 7%. Part of my research funding comes from METAvivor, Inc. and a portion comes from the Susan G. Komen Foundation.”

Drs. Watters and Weiss have collected samples from musculoskeletal oncology patients at UPMC and included them in their biospecimen tissue bank. “We are sequencing them in an attempt to match them to the original primary tumors they had in the breast,” stated Dr. Watters. “Bone metastases can occur 10-15 years after the primary tumor, so we are delving into the archives for samples in order to have 20 matched pairs.”

“Thus far we have identified cohorts of patient samples and found groups of genes that are upregulated, with their expression levels being higher in the metastases compared to the primary tumor. A lot of patients become resistant to treatment so that the original treatment for the primary tumor may not be effective. It’s the metastatic tumor that kills them.”

New targets…

Because the original treatment given for the primary tumor is not effective for the metastases or is not getting to those tumors, says Dr. Watters, new targets are needed.

Dr. Weiss commented to OSN, “One basic concept is this idea of resistance to cellular stress. If you are a bone cancer cell in the tibia you are trying to find a way to the lung…so you exit the tumor and find a blood vessel leading to the lung. Then you ‘crawl out of’ the blood stream and start growing—all the while the chemotherapy is trying to kill you. One of the enzymes we all have that allows cells to detox and guard against oxidative stress is aldehyde dehydrogenase (ALDH). We looked to see if less metastatic osteosarcoma cells have less ALDH than very metastatic osteosarcoma cells. In fact, the highly metastatic cells were just cranking out this enzyme and the less metastatic cells grew but didn’t spread and did not have much ALDH.”

“Then we looked at patients in our tumor registry and tissue bank, individuals whose outcomes were already known. In reviewing 10 patients, some metastatic, some not, we examined the ALDH in their cells. We found that those who metastases had high ALDH!”

Eureka…what’s next?

Their minds reeling, the researchers then asked, “What do we know inhibits ALDH? Antabuse…a drug used to combat alcoholism. If a heavy drinker takes Antabuse, he or she gets very ill because the alcohol never gets metabolized. So we started looking at cells in culture and then in mice with osteosarcoma. We wanted to determine if Antabuse was active in killing the metastatic osteosarcoma cells and to find ways to improve on that so as to target those highly metastatic cells. It is not necessary to kill every cell in the tumor….you just have to kill the ones that want to leave the tumor and cause trouble elsewhere in the body.”

Their other fundamental area of research is that of developmental pathways. Dr. Weiss: “It is unlikely that every cell in a tumor is capable of metastases as there is so much heterogeneity in tumors. And in terms of genetics and what the cells can do there is a lot heterogeneity. So which cells do you have to kill? These metastatic cells display resistance to stress, the ability to grow, and the ability to replicate, the same qualities that stem cells possess. So, we then began to look at stem cell markers.”

“We began examining the mammalian target of rapamycin (mTOR), the NOTCH pathway, and the occurrence of sarcoma-associated cachexia (wasting syndrome). Cachexia, which affects 50% of cancer patients, is frustrating for patients and family members as it doesn’t matter how much the person eats…the body goes into starvation mode—obviously not good when they have to undergo surgery or chemotherapy.”

“Then we looked to see if there was cachexia in our sarcoma patients and found that it was present in 40% of those individuals. So we examined the tumor and cultured cells in those who had cachexia and those who did not. The Notch pathway is very important in muscles so when the Notch signaling is too elevated the muscle stem cells do not differentiate into normal adult muscle cells—and we need a pool of stem cells to draw from when muscle is injured.”

“In earlier research we had determined Notch signaling is significantly higher in sarcomas, so we thought that perhaps the tumor is elaborating something that is causing the cachexia. Indeed, we found that patients with sarcoma-associated cachexia had higher Notch signaling. What we didn’t expect was that there was a huge correlation between the clinical event of cachexia and the clinical event of metastases; none of the patients who didn’t get cachexia had metastases. Also surprising was our finding that if you co-culture sarcoma cells with muscle-derived stem cells—whether the patient has cachexia or not—it jacks up their Notch signaling expression and keeps them from differentiating into normal muscle cells.”

Dr. Watters added, “At the moment we are validating a larger cohort of samples for both our metastatic breast cancer and sarcoma projects. We are sequencing new patient samples again to see if the top gene candidates ‘pop up’ again. In addition, we are creating a ‘tissue microarray’ so we can take samples from patients with tumors and put them on one small slide and do staining for specific proteins.”

And her message to orthopedic surgeons?

“These patient tumor samples from bone are extremely valuable resources that are often difficult to obtain unless you are an orthopedic surgeon or collaborate with one. The more samples that we have to sequence and study then the better our ability to identify novel targets to tackle these cancers that go to bone or originate in the bone. Please keep this in mind and reach out to any scientific partners at your institution or elsewhere to foster collaborations and to establish a pipeline for collection and analysis.”

Dr. Weiss’ message? “All cancer researchers should pay more attention to metastases. Nobody dies because of the primary tumor…it’s the metastases that do it.”

“I am an above the knee amputee,” says Dr. Weiss, “having lost my right leg to complications of all the osteosarcoma operations. So, I guess you could say that, while it didn’t kill me, it really pissed me off.”

And, says Dr. Watters, every two minutes someone dies from metastatic breast cancer.

We should all be pissed off.