Partnering for progress

When Saul Rosenberg, Executive Director, Oncology Discovery, and his team at AbbVie began investigating a new way to restore cancer cells’ ability to self-destruct, they had a feeling they were onto something. What they didn’t know was just how big the idea was – and how far down a new path it would take them.

Every day, cells die in our body, making room for new, healthier cells. This process – called programmed cell death or apoptosis – is typically controlled and predictable in multicellular organisms.¹ But what happens if that carefully-regulated process stops working? The cells that should naturally die, don't. Left to their own devices, they can build up in our bodies causing tumors to develop. Many of those tumors become cancer.^1,2

Rosenberg and his team hoped that by understanding the pathways involved in apoptosis, they could begin to find ways to treat different forms of cancer. Their exploration brought them to a target: a protein called B-cell lymphoma 2 or BCL-2, which tends to bind to and neutralize the proteins that aid in apoptosis, limiting their ability to initiate the process.^3,4

At the time, no one else was investigating a way to block BCL-2. So to further their investigation, Rosenberg and his team began sharing several of their BCL-2 inhibitor molecules with scientists at other universities and academic centers. Together, perhaps they could gather more data and determine which of these molecules to move forward with.

That decision to collaborate launched a journey that spanned nearly two decades, the formation of a tight-knit group of scientists across institutions and the creation of a whole new scientific approach. With a clear first step and a unified goal, the group got to work.

The AbbVie team spent nearly a decade exploring different ways to inhibit the BCL-2 protein pathway. Along the way, they began a collaboration with Anthony Letai, M.D., Ph.D., Professor of Medicine, Harvard Medical School and Department of Medical Oncology, Dana Farber Cancer Institute.

Working first from his mentor Stan Korsmeyer’s lab at Dana Farber, and then later from his own, Letai tested a number of the potential inhibitor compounds on a variety of primary patient-derived samples. This type of testing on patient-derived cells, called ex vivo testing, played an essential role in building the case for this program.

Utilizing an inhibitor molecule invented by AbbVie, the Letai and Rosenberg teams successfully demonstrated that inhibiting this particular family of proteins allowed some tumor cells to die.¹⁰

That’s when Michael Andreeff, M.D., Ph.D., Professor of Medicine; and Marina Konopleva, at that time Assistant Professor, Department of Leukemia and Stem Cell Transplantation at the MD Anderson Cancer Center, got word of the progress and grew intrigued by the early results of this compound.

Drs. Andreeff and Konopleva reached out to share their interest in the role this family of proteins plays in AML, a disease caused by abnormalities in an early stage of myeloid cells in the bone marrow. This form of leukemia is especially aggressive and difficult to treat. There was already evidence that the BCL-2 protein is overexpressed in a high proportion of AML cases,^5,6 and elevated levels of the protein had correlated with poor prognosis and resistance to chemotherapy.^7,8 The critical need for progress was clear, so Rosenberg sent samples of the compound to Houston, and with that, MD Anderson became a partner in the research efforts.

As pre-clinical research across organizations continued, the teams confirmed that this molecule could be effective in helping cancer cells die.¹¹ Unfortunately, it also appeared to be causing thrombocytopenia, abnormally low levels of platelets in the blood.³

The AbbVie chemistry team, led by Andy Souers, Ph.D., started a new search for a different inhibitor molecule. By 2009, they had developed and tested a compound that inhibited the growth of BCL-2–dependent tumors in vivo yet spared human platelets.³

By 2011, the teams finally saw the testing of their molecule begin in a clinical trial for people with chronic lymphocytic leukemia (CLL).

While data were being gathered on CLL, Joel Leverson, Ph.D. and a team of biologists at AbbVie continued the search for other tumor types that might respond to the same mechanism of action. Part of that search involved collaborations with top labs outside of AbbVie, including Letai’s and Konopleva’s. “We have great labs here and tons of resources, but we cannot know everything,” says Leverson, now scientific director, oncology development at AbbVie. “The field is so large that it’s important not to operate in a bubble. We’ve made it a priority to engage with the wider scientific community.”

With AbbVie in the northern suburbs of Chicago, the researchers at MD Anderson in Houston and the team at Dana Farber in Boston, close communication was key.

“I remember running into Marina Konopleva for the first time at a conference. It took seeing her face-to-face to realize that she was as excited as I was about this new approach in AML… both of us really saw an opportunity to make a change,” Letai says. “We exchanged a lot of emails, a lot of data, and we divided up the work between our three organizations’ different labs.”

MD Anderson and Dana Farber had been gathering preliminary data for a few years in AML. It was time to show AbbVie the potential. So, Letai flew from Boston to Chicago and presented data from both his and Konopleva’s labs.

“That was a turning point for me,” Letai says. “Going from a laboratory project to actually doing something I had wanted to do my entire career – help impact the landscape in hematology for patients.”

Konopleva’s lab at MD Anderson began testing the compound with primary patient-derived AML samples. In December, the whole group convened at the American Society of Hematology Annual meeting and reviewed the data in AML. They were all in agreement: it was time to start clinical trials.

The researchers began clinical trials in AML.

“At the time, some experts told us not to bother with acute myeloid leukemia. It’s such a difficult, aggressive disease,” says Hagop Kantarjian M.D., Department Chair, Department of Leukemia, MD Anderson Cancer Center. But Kantarjian, Konopleva and their teams believed there was enough pre-clinical rationale to investigate further.

With clinical trial data in hand, Konopleva and Kantarjian, along with the AbbVie team, met to determine if the program should move forward.

“I was quite disappointed that the clinical responses with the single agent were not as profound as we had predicted them to be in the lab. But that was the truth we had to take, realizing how difficult AML is to treat,” Konopleva says.

So, the group began a new round of clinical trials, this time taking a different approach.

Clinical trials in multiple centers, championed by the MD Anderson team with Dr. Courtney DiNardo, Konopleva and Kantarjian; and Letai at Dana Farber, continued for the next 4 years.

For AbbVie’s Leverson, smart partnerships and cross-network collaborations made all the difference in bringing this program in AML to life.

“From where I sat, it was amazing to see the number of people who contributed to this program – chemists and biologists, pharmacologists, biomarker scientists – and to see what the scientific community can come together to do,” he says. “I’m really proud to have just been a part of it.”

“I think one of the strengths of this program is that we started it at a company that would let us do more than a decade of pre-clinical research,” Rosenberg says, who has seen the program through from early apoptosis research to clinical development. “The philosophy was always, ‘follow the science.”

While additional clinical trials continue, those involved in the research hope to one day see the impact of their collaboration.

“This is what you dream of as a scientist,” Letai says. “That the decades of work, countless conversations and thousands of hours dedicated by teams across the country might make a difference in the lives of patients, especially those with fewer options for treatment.”

1. Cory S, Huang DCS, Adams JM. The Bcl-2 family: roles in cell survival and oncogenesis. Oncogene. 2003;22:8590-8607.
2. Hanahan D, Weinberg RA. The hallmarks of cancer. Cell. 2000;100:57-70.
3. Souers AJ, Leverson JD, Boghaert ER, et al. ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets. Nat Med. 2013;19(2):202-208.
4. Plati J, Bucur O, Khosravi-Far R. Apoptotic cell signaling in cancer progression and therapy. Integr Biol (Camb). 2011;3:279-296.
5. Campos L, Rouault JP, Sabido O, et al. High expression of bcl-2 protein in acute myeloid leukemia cells is associated with poor response to chemotherapy. Blood. 1993;81(11):3091-3096.
6. Mehta SV, Shukla SN, Vora HH. Overexpression of Bcl2 protein predicts chemoresistance in acute myeloid leukemia: its correlation with FLT3. Neoplasma. 2013;60(6):666-675.
7. Schimmer AD. Novel therapies targeting the apoptosis pathway for the treatment of acute myeloid leukemia. Curr Treat Options Oncol. 2007;8(4):277-286.
8. Del Poeta G, Venditti A, Del Principe MI, et al. Amount of spontaneous apoptosis detected by Bax/Bcl-2 ratio predicts outcome in acute myeloid leukemia (AML). Blood.2002;101(6):2125-2131.
9. Dohner H, et al. Acute Myeloid Leukemia. New Engl J Med. 2015; 373:1136-52
10. Rosenberg S,. et al. Inhibitor Bcl-2 reduces tumors. Nature. 2005; 435:677-681
11. Konopleva M, et al. ABT-737 in AML. Cancer Cell. 2006. 10(5):375-88

Jack Hirschfield
Email: jack.hirschfield@abbvie.com
Call: + 1 224-458-0943

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