Science, serendipity and a strong sense of patient needs

Published on 12/12/2022

For Shiva Malek, breakthrough drug discovery hinges on three key elements: “Fundamental research, technological innovation and sticking with the tough problem,” she told live magazine during an interview this summer.

But the Global Head of Oncology at the Novartis Institutes for BioMedical Research, who joined from Genentech earlier in 2022, also knows that serendipity can tip the scale. “Of course, serendipity is not a strategy. But if you stick with a problem, you can seize the opportunity when it presents itself.”

Serendipity struck time and again during her professional and private life. As a child, while on holiday in the United States visiting relatives, the revolution in her home country Iran broke out, forcing her family to stay there for good. While she admits having gone through a rough phase initially, Malek distilled valuable lessons from this challenging period.

“Our immigration story was different from most, as it was serendipity. Yet, it was still difficult for a family from Iran,” Malek remembers. “This, however, drew you to your community quite a bit. So beyond just family, there was an Iranian community there, which taught me the value of this group, the value of a network and how this can influence you.”

This experience is still reverberating today. “Some of those fundamental principles also influence how I operate as a leader today,” she said. “What stayed with me was the importance of the team, the importance of a network, and the close ties you can build.”

Growing up in the small town of Logan, in Cache County, Utah, with her two sisters, another happy coincidence emerged from this early childhood period. “As a kid, my two sisters and I would play outside quite a bit as Logan is a really rural community. Through play, I realized how much I was drawn to exploring and creating things and sensed an unsatiable curiosity in me.”

The fact that English was her second language would also cement her professional yearning as she discovered her love for science. “English was a second language for me. So, I remember, early on in school, it was much easier for me to follow math and science. But I also realized that my interest in these subjects was a strength I had.”

After moving to California with her family, her interest in science grew. “In California, in middle school and high school, I really enjoyed the science classes. We were dissecting animals. Even in elementary school we did some of that. I enjoyed this exploration piece.”

She later majored in biochemistry as an undergrad at the University of California, Los Angeles, UCLA, and initially considered pursuing a career in medicine. “At the time, I didn't know that there was a career in industry or biotech. That wasn’t an option. Nobody did that.”

But serendipity would once again open its doors when Malek started working in the lab of Juli Feigon at UCLA. “I was 17 when I started college, so I didn’t understand any of this at all. But now, looking back at that experience, I think, wow, what an amazing person she was! I don’t remember any other woman on that floor, or in that building. She was tough, but also incredibly smart. And I just learned a ton from her.”

One of the key lessons she took away during these early years with Feigon was a disciplined approach to science. “The fundamental principle, I think, which inspired me there, was this concept that if we understand biology at the fundamental structural level, we can ultimately link that to disease.”

This idea has never left her as she proceeded to continue her MSc and Ph.D. studies at the University of California in Irvine and later at University of Califor­nia, San Diego, before she took a job in industry. This included stints at Vertex and later at Genentech, where she stayed for 15 years in cancer research, having achieved notable discoveries in the oncogene space.

These experiences together with her deeply scientific, curiosity-driven mindset will also be her guiding light as she continues her leadership at NIBR.

Dr. Malek, you started your scientific career in academia and soon moved into the cancer space in the pharmaceuticals industry. What has been driving you all these years?

What I love about science is that there is a final answer. There is a solution to a problem you encounter. And it’s not subjective. It’s not based on opinion. It’s data that drives the final answer. This has fascinated me from my childhood onwards and has shaped my thinking throughout my career.

Why did you choose to move in the oncology space?

Oncology is a field where we have a clear understanding that genetic mutations cause cancer. This then begs the question, what are these mutations doing to protein structure and function? And we can study that and understand it at a single amino acid level. That just blows me away.

How is this linked to drug discovery?

The fact that we can understand the fundamental mechanisms at the atomic resolution level, and then think about designing drugs selectively for a mutated oncoprotein is really like a dream. That always kind of inspires me. But on top of that, today, more than ever, we have so many new technologies available to us, such as cell and gene therapies or radioligand therapies. This is opening exciting new opportunities and approaches to cancer drug discovery.

Most people cover their ears when they hear the word cancer. How do you cope with the disease on an emotional level?

I’ve been touched by cancer in my life too. My best friend from college, as an undergrad, was diagnosed with breast cancer. She was in her 20s. It left a big mark on me. Also, one of my closest collaborators at Genentech, a really dear friend, suffered from breast cancer for years. I still remember how she told me: ‘If I just keep taking these medicines, and nothing changes, everything could be fine. I’ll be fine.’ Unfortunately, she had a recurrence and succumbed to the disease. She was my age and had two young girls. So, while emotionally it is difficult, the personal nature of this disease is also what keeps me committed to tackling some of the biggest scientific challenges despite the significant technical hurdles.

How does this affect your work?

For many cancers, we don’t have lasting efficacy over time. While my friend was fine for a few years, she eventually succumbed to the disease. That was hard to see. Towards the end, she was working on figuring out how to cure her own disease. For me, this really means that we need to direct our effort and energy and our resources towards discoveries that really make a difference in patients’ lives.

What does it take to make the efficacy of new therapies longer-lasting and really make a difference for patients?

Drug development is hard, and we need to play the long game. From a scientific point of view, I think that the story around the development of an inhibitor for the oncogene KRAS offers valuable lessons. For decades, scientists worked on this holy grail of cancer drug discovery before the first big breakthrough was achieved in 2013. But some doubted that this discovery could lead to the development of a drug because Kevan Shokat, who discovered the mechanism, targeted the inactive state of the protein.

Why were scientists so skeptical?

Mutations in KRAS were known to “lock” KRAS into an active state and hence it seemed unlikely that targeting the inactive state would have therapeutic benefit. But it turned out that the specific mutant version of KRAS, KRAS-G12C, that Kevan screened had some unique features that at the time were not known. And as luck would have it, these unique features made KRAS-G12C sensitive to inhibitors of the inactive state. I don’t believe that even Kevan knew this when he started the project, so in part serendipity played a role. Of course, serendipity is never a strategy, but it can come as a result of a strategy. What is a strategy, however, is to really commit to something that you know is fundamentally important. We all knew in the industry that targeting mutant KRAS was going to benefit patients. So that’s why you commit to a problem like that, even if it takes two decades to get there.

How will you leverage this experience going forward at NIBR oncology?

Staying focused and invested in key drivers in cancer that have a direct genetic link to disease. Tackling major scientific challenges from different angles, both from leveraging novel technologies to spurring collaborations to leveraging the best science. While not every problem merits this kind of commitment, a strong understanding of the underlying biology should give us a degree of confidence to continue pursuing it. Those are the things that you don’t walk away from.

You mentioned new technologies. What do you expect from them?

I think Novartis has a flurry of new technologies that can make a difference for patients. Just take our new T-Charge platform in the cell therapy space, which can reduce the manufacturing timeline and the cost of production for a therapy. This helps patients to get drugs faster. Also, in the nuclear medicine arena, we can not only expand the disease space, but continue to develop the therapy in novel ways by using different kinds of radioactive particles that can have a stronger and broader effect on cancer cells.

Are there other advantages coming from these platforms?

Yes. Our technology platforms enable us to build combinations of therapies with differentiated and orthogonal mechanism of action. Further, we know that cancer is a complex and heterogeneous disease, and that one technology or approach alone is not sufficient to drive long-term response in patients. Since each technology platform has its own advantages and disadvantages, we can choose the right platform(s) for specific cancer types (i.e., lung cancer versus breast cancer) or genetic contexts.

Where do you see other uses for novel technologies?

I think we should also start to use our technology and tools more intensively to understand why patients respond and how they become resistant to existing drugs. I think it’s fundamentally important to iterate on those learnings and build on that. We need to improve on those drugs and build that next generation of molecules.

Is this also linked to your idea of sticking to a problem which one can fundamentally understand?

Yes. I think this notion of sticking to a problem, and really understanding it, particularly in patients, and taking those lessons learned to figure out how we can improve upon it, is of paramount importance. Novartis had great breakthroughs in the past such as Gleevec. And I think we need to continue distilling the lessons learned from these medicines.

How can you balance this drive for innovation with the overall need to have a real impact for patients?

I think this is one of the most exciting and challenging aspects of our jobs. It is a paradox that we are living where we have to balance our desire for innovation – i.e., following the science, making fundamental discoveries and developing new technologies – with a focus on developing highvalue and transformative medicines for patients. These two aspects of our work create a healthy organizational tension, forcing us to clarify the level of scientific risk and degree of innovation we are willing to take in the context of patient impact. I still remember what my college friend said when she told me about her breast cancer diagnosis. She said: ‘I’m not stopping my life. I am going to choose to live.’ This still gives me the chills and I think about that all the time. If we can make that statement easier for a patient and give them that choice to live, then we have made a difference. I can’t think of a better job in the world than to have a chance to do that, to give patients that choice to live.