All in the Family
Robert Orlowski’s Unlikely Path to Myeloma’s Pantheon
Fall in love with some activity, and do it! Nobody ever figures out what life is all about, and it doesn’t matter. Explore the world. Nearly everything is really interesting if you go into it deeply enough. Work as hard and as much as you want to on the things you like the best. Don’t think about what you want to be, but what you want to do.
~ Richard Feynman
“I remember, Bart Barlogie stood up,” recalled Robert Orlowski, “and said, ‘This is a real drug.’ And that's what got things going.” It was at a gathering of myeloma experts at the annual meeting of the American Society of Hematology (ASH) in 2000.
The “real drug” was an investigational agent, PS-341, long before it would be called bortezomib[1] or its brand name, Velcade. Approved by the Food & Drug Administration (FDA) in 2003, it is now a so-called backbone drug, critical to the development of combination therapies and the second-most used drug in myeloma treatment.
Orlowski’s University of North Carolina at Chapel Hill (UNC) clinic was, “at least at that time, a relatively obscure myeloma center.” Barlogie’s divine-like seal of approval must have felt similar to what a British subject might experience when the blade of a sword briefly rested on the shoulder in a knighthood ceremony.
After all, Orlowski was something of an outsider when it came to myeloma. Just a few years earlier, Barlogie and his colleagues in Arkansas had shaken the myeloma and cancer worlds by demonstrating the anti-myeloma effect of thalidomide, an old drug with a notorious past. And that had only happened once before in more than 150 years in the known history of the disease, almost 30 years earlier when Daniel Bergsageldiscovered the therapeutic benefits of melphalan.
In the cancer research equivalent of an instant, the PS-341 earthquake shook the myeloma world, setting off a flurry of activity in myeloma circles around the globe. As Orlowski summed it up, “we had relatively very few drugs. Frankly, at that time, it was very frustrating to treat because you had VAD and thalidomide and then after that, you were done.” Even the then-controversial procedure of stem cell transplantation was an option available in very few clinics. “That’s basically what treatment was.”
And to top off the audience’s surprise at that ASH gathering, Orlowski had no formal connections to the academic lineage of the three American giants in myeloma: Barlogie, Robert Kyle, or Kenneth Anderson. But that’s not to say he didn’t have a strong pedigree.
On paper, Orlowski’s intellectual bona fides were impeccable. He followed his youthful passion to understand the stuff of human biology, which led to Columbia University for undergraduate chemistry, Yale University for a PhD in Molecular Biophysics and Chemistry as well as an MD, Washington University in St. Louis for his medical internship and residency, and postdoctoral fellowships in oncology and hematology from Johns Hopkins University in Baltimore.
Orlowski worked under Chi Van Dang, a native Vietnamese researcher whose lab at Hopkins was on the cutting edge of cancer cell genetics. Dang’s work built on discoveries made by Harold Varmus and J. Michael Bishop. Both were awarded the Nobel Prize for Medicine in 1989 “for their discovery of the cellular origin of retroviral oncogenes,” the foundational basis for all cancer research and treatment today, i.e., that all cancers have a genetic origin.
Dang is a pioneer in the identification of MYC (pronounced mick), a transcription factor, or protein, that converts a cell’s DNA into RNA. For a student with Orlowski’s background and aspirations, there was no better place to be. Dang’s lab focused on understanding how cancer cells divide and conquer, multiplying from one cell to become a lethal army. His work continues today.
“Chi gave me a project – frankly I don’t even remember what it was, but it did not work out – that got me interested in the degradation of MYC,” said Orlowski. To better understand what degradation in cell biology is, try envisioning what happens to food when it flows into a sink’s garbage disposal. It may not sound glamorous when put that way, but in cell biology it’s essential to make the human system function normally. Just as it is has been in human society since the discovery that rats with fleas proliferating in unhygienic cities in Europe caused the Black Death in the 14th century.
All human cells have life cycles ending in death. The “garbage disposal” is the proteasome. That’s where Orlowski focused his attention. He called another scientist he knew who worked on proteasomes “and had him send me some of the inhibitor that he had made.” Inhibition stops the function of the proteasome. “I treated some cells with it and, not surprisingly, MYC levels went up, because it was digested through the proteasome.”
Orlowski’s lab work “compared MYC-transformed to non-MYC-transformed controls,” turning them “off and on,” which confirmed “cell death occurred as a result of proteasome inhibition preferentially in the MYC-transformed cells. And that was both in vitro as well as in vivo” – in Petri dishes and in living organisms.
“We used a Burkitt lymphoma[2] model,” said Orlowski, “at the time it was the first validation of in vivo activity of a proteasome inhibitor.” He “was looking for faculty jobs to pursue this area further.” His timing couldn’t have been better, for him and, as it turned out, for myeloma patients everywhere, although neither he nor they had any idea of a connection yet.
Just a few years earlier, Orlowski began interviewing for jobs as he was nearing the end of his Hopkins fellowship. “When I said I wanted to study the proteasome and inhibitors, they looked at me like I had three heads,” he laughed. He remained adamant, “this is too important a mechanism to the homeostasis[3] of not just cancer, but normal cells.” Attempts at inhibition had been “way too toxic. We were using drugs like cyclophosphamide and dex [dexamethasone], which were not exactly tumor specific.”
Thankfully for posterity, one interviewer didn’t put Orlowski into a box of freaks. “I wound up at UNC because Al Baldwin, at that time, “was working on nuclear factor kappa B (NF-κB)[4] in proteasome inhibitors.”
Baldwin introduced Orlowski to Alfred Goldberg, a Harvard-based cell biologist who was a leader in the study of protein degradation in cells. Baldwin thought Goldberg, who founded a company called Myogenics[5] would be interested in exploring the development of protease inhibitors into drug candidates, and he might be interested in Orlowski’s work. Goldberg turned out to be a matchmaker, introducing Orlowski to two pioneers in drug development.
Peter Elliott, a Welsh-born pharmacologist, was a trailblazer in transforming monoclonal antibodies into drug treatments, and Julian Adams, was the creator of one of the first effective AIDS antivirals in the early 1990s which is still used successfully in combination with other drugs today. Together they formed a drug development company, ProScript, which was exploring use of a small molecule they owned “for cancer purposes,” Orlowski recalled.
“Frankly, they were on fumes,” Orlowski went on, “I said, ‘let’s try this in other hematological malignancy patients,’ and they said, ‘fine, were happy to do it, we’ll give you the drug and we’ll do PK and PD assays” – tests to determine where, how, the speed and in what amounts drugs end up. There was only one small problem. “We didn’t have the money for a clinical trial, so I applied for a grant from the Leukemia & Lymphoma Society, they approved it, and that gave us the money we needed. I’d always been interested in heme malignancies, but I hadn’t especially focused on myeloma.” The new drug was ProScript’s 341st tested drug candidate – PS-341.
Elliott and Adams “were enthusiastic about it and were good to go,” as was a young, relatively unknown Orlowski. “Their hypothesis at the time was that because the proteasome was involved in breakdown of muscle protein, which was true, that by blocking that you might have an impact on cancer cachexia,” literally starving cancer cells to death. “That didn't work out,” but once they were made aware of Orlowski’s work in Burkitt lymphoma, using “PS-341 for cancer purposes was something they were interested in.”
Soon after arriving at UNC, Orlowski began a small phase one clinical trial that “showed no activity” in the first three patients enrolled. “The fourth patient was the first myeloma patient we treated,” he recalled fondly, “a really lovely lady who had been referred for a stem cell transplant and traveled in a van with her husband from South Carolina all the way to Chapel Hill. Unfortunately, she had so much refractory disease that we concluded she was not a candidate for transplant.”
But since “she had no prior experience with PS-341, she consented to enroll in our study. We treated her with what would now be considered the equivalent of two cycles of bortezomib, sent off her blood tests, and from a large monoclonal protein at baseline, there was no monoclonal protein after the two cycles. Back then, a complete response, even in newly diagnosed disease, was rare, let alone in relapsed-refractory disease.”
Orlowski’s first thought was: “No, the lab screwed up. They must have switched the sample. This can't be right. Since, we were not that optimistic, we did it again.” To his amazement, this time it “came back with the same result. No monoclonal protein! We did a bone marrow biopsy and she had a complete remission compared to a baseline with lots of involvement. And then I sent her back to transplant, but my colleagues told me she was too healthy for one! We actually presented at ASH solely on the basis of that one complete response.”
For a deadly, at the time mostly hopeless, cancer like myeloma, Orlowski reflected, “even this single agent was a huge advance.” It put UNC on the myeloma map. “We had lots of people referred to us and, in the standards of that time, we became a big myeloma center. Fortunately, the activity was reproduced; ultimately we had nine myeloma patients on that study. All of them had at least some evidence of response, either a reduction in the M protein or bone marrow involvement – although not all of them would have met the now-defined criteria for response, which back then were less well defined.”
It could be argued that PS-341 was something of an extension of a family business, one that was grounded in discovery and creation of a new map in cellular biology. Like so many great achievements in science, serendipity almost seemed to be preordained by a sort of fate. To add to the sense of mysticism, fate went back much farther than Orlowski’s connections to Baldwin, Goldberg, Elliot and Adams.
At its starting point, myeloma, much less cancer or disease, weren’t even imagined as possible destinations. Especially since the Cold War played a strong supporting role in its destiny.
Not that he had any say in the matter, Orlowski came into the world in Wroclaw, Poland in 1963, six months too late to be a native-born American citizen. On the other hand, in terms of simple math, his proto-gene could be, so to speak, considered as American.
Nine months before his birth, his parents were living in Boston. His father, Marian (pronounced mah-REE-ahn) Orlowski, was a Polish MD and researcher nearing the end of a biochemistry fellowship at Tufts University studying under Alton Meister, a pioneer in biochemistry. He was joined by his wife, Jadwiga Uszkiewicz, also a doctor who was active in rehabilitation medicine, focusing on the spine and paralysis. It was a relatively rare couple – since both were MDs – for its time, especially outside of the Iron Curtain.
“My parents met in medical school at the University of Wroclaw,” Orlowski explained, “fell in love and got married. Looking back, one of the few good things about communism back then was if they thought you had an aptitude for something, they gave you training for it. She became a physician at a time when, had she been here in America, there would have been many more challenges for her to become a doctor as compared to Poland.”
Conversely, “one of the things communists expected in order to advance was to be in good standing, which meant being in the communist party,” Orlowski said about the realities of the time. After their fellowships were completed, the Orlowskis returned to Poland. Five years later, they were caught up in the political turmoil caused by the Prague Spring of 1968, a spontaneous uprising of politically- and economically-motivated mass protests unleashed by a political liberalization in Czechoslovakia.
Waves of discontent rolling across the Iron Curtain were felt in neighboring Poland. “Neither one of my parents were, shall we say, particularly enamored with communism. And my father was Jewish, which made him especially problematic,” said Orlowski. In a less deadly, but still serious, echo of the second World War, “there was another wave of anti-Semitism in the country because the communists, of course, had to blame somebody for bad economic times. And Jews like my parents were then a very easy target.”
Marian Orlowski “got in touch with Alton Meister, who, by this time, was at Cornell.” Meister was instrumental in obtaining a Rockefeller fellowship for him. The common procedure for citizens in Iron Curtain nations who traveled outside of it was to “let one person go, but the family would not be allowed to go,” making them virtual hostages. Yet when they applied to travel together as a family, they were pleasantly surprised to get official approval. “I think it was because he was Jewish and considered undesirable.”
His father’s “colleagues had a going away party for him when our visas showed up at the last minute. So, of course we left and took just a couple of suitcases with us.” But as anyone familiar with that era knows, nothing was done until it actually was.
“My mom didn't even tell me where we were going, because she was afraid that I would innocently say something and get us in trouble,” he continued, “so the cover story was that we were going to visit an aunt out in the countryside. Not even in a different country. That’s how we wound up in America.” Plus, they had no intention of returning, especially since they stayed together.
Luckily for his mother and father, “at that time, because there was a physician shortage in the U.S., there was a fairly straightforward path to citizenship for foreign medical graduates. You just had to take an English proficiency test, redo residency – which is not dissimilar to how things are now. That's how we wound up becoming U.S. citizens.”
After his fellowship with Meister was completed, Marian Orlowski spent a few years at Cornell before being offered “a position at Mount Sinai in New York City, which is where he wound up for the rest of his career until he retired.”
Now, as the radio broadcaster Paul Harvey used to say in his distinctive voice years ago, we get to the rest of the story.
Marion Orlowski “was interested in the processing of hormones in the pituitary gland, which are made as essentially precursors, a fusion of proteins that are cleaved by proteases into the mature hormones. He was interested in understanding what proteases were involved in that cleavage process.” An essential part of his work seems a bit primitive when seen from today’s perspective.
“He would buy pituitary glands from slaughterhouses and grind them up. These were,” Orlowski explained, “very classical biochemistry techniques.” He engaged in the tedious work of isolating the parts of cells. To better understand how the proteins broke down, he developed a way to synthesize small protein chains to analyze how they were digested in the cell.
The splitting of the proteins “would release, naphthylamine,” a dye that is part of Congo Red, a stain that is used to identify connections of certain proteins, which are, interestingly, central to the development of AL amyloidosis, which belongs to the “family tree” of plasma cell disorders that include myeloma. In cell biology labs, naphthylamine is used to “understand the kinetics of the process” and “changes in the sequence of the amino acids” by seeing how the cell metabolizes it.
Together with “his main collaborator, Sherwin Wilk,”[6] Marian Orlowski went on to identify a core enzyme in this cellular disposal unit, the proteasome. “That was what he did for many years,” said Orlowski. “One of the things he found was that while most proteases are small,” was a very large and complex protease that functioned as the cell’s so-called garbage disposal, which involves breaking down cellular proteins into amino acids.
Among their most significant achievements was the identification of caspase activity, proteases that play a central role in cell death.
“At that time, nobody knew about caspases,” clarified Orlowski. Since “everybody thought proteases were small molecules, he sent a paper to top scientific journals and was routinely rejected because the dogma was: proteases were small and he was trying to convince people that this huge particle with multiple, different proteolytic activities was really present.
“He wound up publishing the paper in a neurochemistry journal because it had been based on studies of pituitaries,” Orlowski explained further, “and ultimately it turned out that what he had found the core particle of the proteasome, now known as 20S.” Subsequent research by “Martin Rechsteiner found the 26s proteasome, which was the 20s core. And then Alfred Goldberg” – who introduced Orlowski to Elliott and Adams – found this garbage disposal ran on the energy source called adenosine triphosphate (ATP). ATP “is one of the most important molecules of life, present both inside the cells and extracellularly.”
As Orlowski sums it up, “my dad found the 20S core, Rechsteiner found the structures that made the 26S proteasome, and Goldberg found the ATP dependence,” i.e., the proteasome needed by ATP to function. The essential research that tied them all together was done by one of Marian Orlowski’s friends, Aaron Ciechanover, an Israeli who received the 2004 Nobel Prize in Chemistry “for the discovery of ubiquitin-mediated protein degradation.” Ubiquitin tags proteins for disposal by the proteasome.
Ubiquitin is a polypeptide, “a substance that contains many amino acids [the molecules that join together to form proteins].” It is, as it name implies, ubiquitous – found in virtually all human cells. According to Orlowski, ubiquitin “marked proteins for digestion, but” Ciechanover “didn't know what actually did the degradation process.”
Which brings us back to the significance of the work on the trash collecting, disposal, and recycling functions of the proteasome and the combined knowledge gained through the work of Marian Orlowski and Wilk, Rechsteiner, and Goldberg. “That’s how we got into inhibitors,” Orlowski concluded. His father, “in addition to making peptide substrates” – the soil, so to speak, on the surface of peptides with bonding capacities – “he would also make inhibitors out of those peptides because one way of understanding how a protease had an impact on biology was by blocking it. He actually made the first synthetic proteasome inhibitors.”
Marian Orlowski “did not think of them as potential drug candidates, he was more interested in a tool, a compound, to understand the biology.” That was, of course, until a young Robert Orlowski made a call, as noted above, to “another scientist he knew who worked on proteasomes.” The recipient of that call, however, was not just “another scientist.” It was his father, Marian.
And now, to reprise Harvey’s ending for each of his radio broadcasts, you know the rest of the story. At least the first important part of it.
When FDA approval of the proteasome inhibitor bortezomib became the drug branded as Velcade in 2003, it was a first for a drug in its class. This ensconced Orlowski in the myeloma pantheon just a few short years after his Hopkins fellowship.
Orlowski wasn’t the first to explore the potential benefits of proteasome inhibitors in cancer treatment, however. Anderson’s lab at Boston’s Dana-Farber Cancer Institute “had been working preclinically on proteasome inhibitors and NFkB as well.” He added, self-deprecatingly, “I happened to get lucky and treated the first myeloma patient with a proteasome inhibitor because it was an area of interest, but I had not focused on that.”
Barlogie’s assertion about “a real drug” was bolstered by Anderson’s group having “published their preclinical data, which showed that PS-341 was a great drug for myeloma.” The sword of myeloma knighthood touched his other shoulder. Although UNC’s myeloma department was growing, he didn’t have “the patient volume and capacity” that Anderson had. Now, though, he wanted to have one.
It came in 2007 when Orlowski got a call from Houston’s MD Anderson Cancer Center, getting “the proverbial offer that I couldn't refuse.” The baton of MD Anderson’s myeloma legacy was passed on – from Bergsagel’s breakthrough with melphalan; to Raymond Alexanian’s first combination therapy of melphalan/prednisone; to Barlogie’s seminal work in stem-cell transplant and high-dose therapy; to Sundar Jagannath’s mentorship of transplanters throughout the world; to Orlowski.
Looking back almost a quarter century later, Orlowski never forgot the significance of his first myeloma patient, “that was what really launched it: one patient with a complete response.” Orlowski’s nostalgia recognizes how things have changed, “there's no way we could have done that under the rules today.”
Some of the current complexity in conducting clinical trials “is good because the landscape is so much more complicated now. You need to make sure that your drug has a potential good fit, either alone or in combination, and that it's going to address an unmet medical need or a certain population where improvements need to be made.”
More than eighteen years after joining MD Anderson, Orlowski is as optimistic as ever, but believes some issues need to be addressed. “It's fascinating because it has been, in cancer terms, like a blink of an eye. Now, complete responses are much more common, even in the relapsed-refractory setting, the concerning thing for me from a drug development perspective is that now phase one studies, which used to be only to define dose and schedule and toxicity.
“Now, if drugs don't have a good response rate in phase one, they don't develop further, even though there may be a good rationale,” Orlowski pondered, “which, on the one hand, I understand because you want to get the most active things to patients as quickly as you can. But on the other, not every patient is going to respond to every drug and I don't think a drug should be killed if it has a good rationale.”
When Orlowski speaks about his work, he often does so in a scientific shorthand few, if any lay persons can fully comprehend. He sees and interprets things most could never imagine. It’s a language he has taught a new generation of leaders who have flocked to MD Anderson to research and treat myeloma and related diseases.
Eighteen years after arriving in MD Anderson, his titles include: Professor in the Department of Lymphoma/Myeloma, the Florence Maude Thomas Cancer Research Professorship, Director of the Section of Myeloma, and Professor in the Division of Cancer Department of Experimental Therapeutics. Current faculty members Krina Patel and Hans Lee are among the most sought-after speakers for patients and professionals.
His teams have been integral in the development of another popular myeloma proteasome inhibiter, carfilzomib (Kyprolis), and virtually every therapy and treatment strategy that have transformed myeloma into a chronic disease for myeloma patients throughout the world in the past two decades.
But we’ll save that part of the story for another day.
Photo: MD Anderson copyright.
Many thanks to Dr. Craig Hofmeister of Emory University’s Winship Cancer Institute for helping me understand the cell biology discussed above.
[1] The “bor-” in bortezomib refers to boronic acid, a peptide that attaches a drug to its therapeutic targets.
[2] Burkitt’s lymphoma is a rare disorder that inhibits development of B cells (white blood cells).
[3] As I wrote last year about endocrinologist Matthew Drake, “Human life’s biological goal – actually, of all living species – is homeostasis, a functional balance of all bodily systems and organs, acting in concert to create a healthy being. When all works as advertised we rarely, if ever, think about it. Until, that is, something goes wrong or becomes unbalanced, ranging from something as insignificant as a growling stomach to the complications inherent in a cancer diagnosis.” Drake recently left Mayo to accept the position of chief of the Division of Endocrinology and director of the Metabolic Bone Service at New York’s Hospital for Special Surgery (HSS), “the world's leading academic medical center specialized in musculoskeletal health.”
[4] “A large body of literature supports the idea that nuclear factor kappa B (NF-κB) signaling contributes to not only immunity, but also inflammation, cancer, and nervous system function.” Benedict C. Albensi.
[5] As Orlowski explained, “the old nomenclature for protease inhibitors started with MG, a dash, and then a number. So, for example, MG-132 was a very popular compound originally made by Myogenics.”
[6] Wilk’s wife, Elizabeth, was, like Orlowski’s parents, of Polish-Jewish origin. Born in 1936, her family was sent to the Warsaw ghetto after Nazi Germany conquered the nation in 1939. Her father, an engineer who once served in the Polish military, died “on November 7, 1941…in the Warsaw ghetto of an unknown disease after being bedridden for five days – probably from typhoid fever.” After her mother was able to obtain a fake Polish identification card, she and Elizabeth were able to leave the ghetto and survived the war with the help of two gentile couples until the 1944, when the Soviet army liberated Poland. In her later years, she wrote a letter to Yad Vashem, the World Holocaust Remembrance Center in Israel, to nominate the two couples for the distinction of “Righteous Among Nations.” As you may recall from our walk in Berlin last year, this honor was conferred on Harald Poelchau, the prison pastor at Plötzensee Prison.