An Insight into the Life and Work of a Medical Pioneer
Born in Sarajevo, Bosnia and Herzegovina, Dr. Srkalovic has become a leader in Hematology and Oncology, with an exceptional career marked by impactful research contributions and continuous academic recognition. His expertise and passion for improved patient outcomes and innovative research make him a true pioneer in his field.
Dr. Srkalovic currently serves as the Medical Director of the Herbert-Herman Cancer Center and Medical Director of Clinical Trials at Sparrow Herbert-Herman Cancer Center and as a Clinical Associate Professor at Michigan State University’s College of Human Medicine. He is also a distinguished member of ANUBiH, the Academy of Sciences and Arts of Bosnia and Herzegovina.
His academic journey began at the University of Sarajevo, where he graduated from the Medical Faculty in 1981. This was soon followed by a master’s degree in 1985 and a Ph.D. degree from Tuzla in 1997. His pursuit of specialized knowledge led him to a residency in Internal Medicine at NEOUCOM Affiliated Hospitals in Canton, Ohio, USA, between 1995 and 1997, and a Hematology/Oncology Fellowship at Cleveland Clinic Foundation from 1998 to 2000.
Dr. Srkalovic began his professional journey at the University of Tuzla’s Physiology Department in 1981, eventually becoming the department’s head in 1990. In 1992, he was appointed as the Vice-Dean for International Affairs. Between 1988 and 1990, he also held a Research Associate position at Tulane Medical School Department of Medicine and VA Medical Center Polypeptide, Endocrine, and Cancer Institute in New Orleans, LA, USA.
However, the advent of war in Bosnia and Herzegovina in 1992 necessitated a shift in Dr. Srkalovic’s trajectory, leading him to continue his endeavors in the United States and Spain. He has held various significant positions at prestigious institutions, including Kent State University, the Cleveland Clinic Foundation, and the Sparrow Cancer Center.
Dr. Srkalovic’s work has facilitated numerous advancements in treating multiple myeloma, other plasma cell malignancies, molecular subtyping of breast cancer, and Castleman disease. His research on the pan-cancer analysis of clinically acquired resistance has garnered significant recognition, demonstrating his profound understanding of the molecular mechanisms of cancer. He also serves as a lecturer on these and similar topics across the USA.
Dr. Srkalovic is an active member of several notable oncology groups, such as Southwest Oncology Group (SWOG), Michigan Cancer Research Consortium (MCRC-NCORP), Eastern Cooperative Oncology Group (ECOG), Alliance National Clinical Trials Network, and NRG Oncology. He frequently presents at major conferences such as the ASCO Meetings and SABCS. His scholarly contributions include numerous monographs, over 100 peer-reviewed papers, 60 abstracts and several book chapters.
He is part of groups that have received grants from the National Institutes of Health (NIH), AFOSR, American Cancer Society, Millennium Pharmaceuticals, Southwest Oncology Group, and, previously, the Research Council of Bosnia.
Beyond his clinical and research pursuits, Dr. Srkalovic works tirelessly to foster international collaboration, particularly within the Balkan region. His involvement in the Targeted Agent and Profiling Utilization Registry (TAPUR) study exemplifies this.
Moreover, he holds multiple positions at prestigious international journals such as Cancer Research (Ad Hoc Reviewer), Acta Medica Saliniana (Associate Editor – 1991 -1992), Current Hematology Reports (Web Alert Editor – 2002-2005), Acta Medica Saliniana (Editorial Board Member- 2012-present), Acta Medica Academica (Editorial Board Member – 2012-present), Biomolecules and Biomedicine (earlier Bosnian Journal of Basic Medical Sciences) (Editorial Board Member – 2012-present), and Cardiovascular and Hematological Agents in Medicinal Chemistry (Editorial Board Member- 2013-present).
In this interview, we will delve deeper into Dr. Gordan Srkalovic’s journey, exploring his groundbreaking research, his experiences in international collaboration, the impact of his work, his personal interests, and his balance between professional and personal life.
Formative Years: Early Influences, Choosing Oncology and Landmark Achievements
With over 25 years of experience in the medical field, what motivated you to specialize in Hematology/Oncology?
There were three major reasons for my interest in Oncology:
• My mom was diagnosed with small-cell lung cancer, and that prompted me to start thinking about ways to help patients with cancers.
• My research at Tulane University with Dr. A.V Schally, Nobel prize laureate in Physiology and Medicine in 1977. Dr. Schally’s laboratory was devoted to endocrine-related cancers, and my role was to lead the receptor lab.
• I am firmly convinced that patients with malignant diseases need and deserve dedicated care more than anybody else.
Looking back, what are some of the most profound changes you have seen in this practice?
The practice of Oncology has changed immensely since I started my clinical journey 25 years ago. Patients with cancers live longer, their lives are more comfortable, and they are, in most cases dying in more comfortable and dignified ways. Our treatments have become generally less toxic and more targeted. Now, they’re based on an analysis of each patient’s unique cancer biology rather than solely on the origin and classification of the cancer. A new paradigm in treating cancer patients is balancing outcomes with quality of life, which is evaluated by patients rather than medical staff. There is also a very strong emphasis on end-of-life care and the patient’s participation in decisions making. Decisions on treatment, care goals, and the ultimate care pathway are made jointly between patients, their families, and caregivers. That empowers patients and families to make crucial decisions. These changes require significant adjustment by physicians and other caregivers, as well as changes in the educational and training process of new physicians.
As the Medical Director and Director of the Clinical Trials Office at the Herbert-Herman Cancer Center, how do you maintain a balance between your administrative roles and your practice as a physician?
My role as administrator of the Cancer Center and Office of Clinical Trials is intertwined with my clinical practice. Clinical practice gives me a unique understanding of practice flow, relationships with patients and families, and expertise in new drugs and treatments that the entire Cancer Center needs to prepare for. My administrative role is to create a vision for the future of the Cancer Center, which will align with the most advanced developments in clinical science and provide our patients with cutting-edge care. At the same time, I must keep channels of communication with the Hospital System administration and assure that appropriate support for the Cancer Center is available. The role of Hospital Cancer Committee chairman puts me in a position to oversee all cancer-related activities and coordinate between different departments involved in any aspect of the care for cancer patients. That is probably the hardest part of my job since my training was clearly focused on clinical medicine. What helps me are my leadership skills previously sharpened at Medical School in Tuzla and through the Bosnian Herzegovinian American Academy of Arts and Sciences (BHAAAS) and gracious help and advice from my mentors, friends and colleagues.
Your career demonstrates a strong focus on breast cancer and multiple myeloma research. What sparked your interest in these areas of cancer research?
My focus at present is the use of genomics in precision oncology and the development of newel ways of the treatment of our patients. Breast cancer is probably the most researched malignant disease, with multiple prognostic and predictive tests based on genomics. Breast cancer research is opening new avenues for innovative approaches to clinical investigations. One of the studies we opened at Hebert-Herman Cancer Center as the only institution in Michigan is I-SPY 2, which is a new adaptive clinical trial platform designed to improve outcomes in high-risk breast cancers in neoadjuvant settings. The trial uses genomic and clinical biomarkers to classify breast cancer into subtypes with Bayesian adaptive randomization to allow an individualized approach.
My interest in Multiple Myeloma started during my Oncology/Hematology training and then continued during my stay at Cleveland Clinic. My interest was ignited by my colleague and friend Dr. Mohammad Hussein, one of the premier investigators and leaders in the field of monoclonal gammopathies. My fascination with the disease was fed by the incredible complexity of plasma cell functions and the almost unreal capability of myeloma cells to adapt to and, at the same time, change the environment they live in. Pathological effects of myeloma cells are produced almost remotely without the direct presence of the cells, making them look like “evil geniuses”. Fighting cells like that and stopping them in their pathway of destruction can consume completely the professional and personal life of the myeloma researcher. However, it’s all worthwhile, as we’ve made remarkable strides in treating multiple myeloma, and patients with this disease are living increasingly longer.
In your work with the FLEX real-world data platform, can you discuss any key findings regarding breast cancer research and their contributions to our understanding of the disease and potential treatments?
FLEX (Mammaprint, BluePrint and Full Genome Data Linked with Clinical Data to Evaluate New Gene Expression Profiles: An Adaptable Registry) is a large-scale, population-based prospective registry that began enrolling patients in 2017. The FLEX study matches full-genome expression data with comprehensive clinical data on patients enrolled in the study. At present more than 13400 patients are enrolled in the study. Multiple reports were created based on data from this study and presented at international meetings. Highlights are:
a) Number (15-29%) of ER +, Her-2 – breast cancers are reclassified as basal type by Mammaprint. These cancers did not have evidence of estrogen receptor (ER) signaling despite IHC positive up to 99% for ER. These cancers clinically behave like Triple-negative breast cancers (TNBC) with high chemosensitivity and pathologic complete response (pCR) rate but poor outcomes if pCR was not reached.
b) Poor outcomes for black women with breast cancer may be due to undertreatment of ER+ Basal cancer if not recognized.
c) FLEX is identifying very important ImPrint immune signatures in early-stage breast cancers.
d) Most importantly, information from FLEX provides treatment physicians with data supporting less and less toxic therapy and possibly withholding treatment in lower-risk patients. In high-risk patients, it provides improved selection tools and methods to address small subsets of patients and enables earlier intervention.
Oncology today and tomorrow
How does the TAPUR study, a significant endeavor in personalized medicine, align with your research, and what are some noteworthy outcomes or insights that have emerged thus far?
The concept of TAPUR (Targeted Agent and Profiling Utilization Registry) is unique. This is the first study ever created and executed by the American Society of Clinical Oncology (ASCO). The leadership of ASCO initiated the study with the idea of testing the practice and utilization of genomic testing in oncology, as well as investigating the use of FDA-approved drugs in this context for patients with no other standard of care (SOC) options. This concept provided patients and oncologists with the option to treat patients with specific somatic gene mutations with FDA-approved drugs targeting that mutations even in cancers of origin where there was no exact approval. Drugs were used based on somatic gene mutations, not based on the origin of the cancer. The advantage of this type of study is that the drug’s toxicity is already established, and the drug is in commercial use, so very few new side effects are expected. That was confirmed in most of the arms of the TAPUR. The general concept of the study perfectly aligns with my clinical research since it is scientifically sound and has immediate clinical effects and possible benefits for my patients whose standard treatment options are exhausted. The study also informs the oncology community about the use of genomic testing in community practice and establishes a baseline for future planning in precision oncology, which will become a central point of treating patients with malignant diseases. Another important aspect of this study is that it opens avenues for using drugs tested in this study to treat cancers that are not currently covered by FDA approvals. The study I presented at this year’s ASCO showed that the PARP inhibitor talazoparib had significant efficacy in 16 solid tumors with BRCA 1/2 somatic mutations, with an overall disease control (DC) rate of 57%. This rate far exceeded the null hypothesis, which predicted a DC rate of only 15% based on previous trials of talazoparib based on cancer type rather than genomic alterations. Future studies will show if these results will be confirmed in a larger cohort of patients and in cancers for which the FDA approval of PARP inhibitors is absent. PARP inhibitors are currently approved for breast, ovarian, prostate and pancreatic cancers with germline BRCA 1/2 mutations.
Your work also involves Castleman disease, a rare condition. What motivated you to focus on this disease, and what unique challenges does it present regarding diagnosis and treatment?
My work with Castleman disease started with an e-mail from a colleague from the University of Arkansas, Fritz Van Rhee, MD, who probably has the largest cohort of Castleman patients worldwide. We had some mutual Castleman patients during my time at Cleveland Clinic and my Sparrow practice. In addition, we both enrolled patients in a sentinel clinical trial of Siltuximab, an Interleukin 6 (IL-6) blocker, for the treatment of HHV-8 negative multicentric Castleman disease. He was treating a young, exceptional physician from the University of Pennsylvania who suffered from an extreme form of Castleman disease, TAFRO syndrome. This young man recovered and devoted his life to fighting against this rare disease. He and Fritz started the Castleman Disease Collaborative Network (CDCN), which comprises experts in this disease covering four continents worldwide. CDCN developed the first diagnostic criteria for Castleman disease, published guidelines for treating both unicentric and multicentric Castleman disease, established a worldwide registry of Castleman patients (ACCELERATE), supported numerous studies related to this disease and published many papers in peer-reviewed journals. The CDCN also serves as a source of information for patients and physicians, and members of the CDCN serve as consultants for colleagues with less experience in diagnosing and treating Castleman disease. I personally received requests for help from multiple countries, from Slovenia to New Zealand and multiple referrals from surrounding states. CDCN also serves as an advocacy group for patients with Castleman, whose voices can be heard much more now. Despite the rarity of this disease, thousands of patients and their families suffered from this, although nonmalignant, still deadly disease, which in cases of multicentric disease has a prognosis almost identical to metastatic cancers. What makes this disease unique is that children as young as two years old could be diagnosed with Castleman. My intention is to continue this very important work in the future and help those who need help most.
How do you foresee the evolution of personalized medicine in the next decade?
I think all oncology treatment in the next decade will be personalized and very specific to individual patients. Cancer is a disease of malfunctioning genes, and our prevention, diagnosis and treatment must be based on identifying those genes. There are multiple complicated aspects of this simplified statement.
First, our current testing often identifies multiple somatic mutations. At present, we do not have a perfect way to identify “driver” mutations that are crucial in cancerogenesis and divide them into “bystander” mutations that do not contribute to abnormal cell growth. Increasing data and the use of machine learning will help us resolve this problem in the future. Another approach that will help us in the future is increasing the number of targeted therapeutic agents and their availability which will allow us to target multiple mutations with better results. That was already shown to be very effective in San Diego I-Predict study.
Second, cancer cells are live structures that go through gene mutations all the time and adjust to treatment pressure by bypassing growth pathway blockade and creating novel ways to survive and grow. This presents the most complicated challenge and will require innovative ways to monitor those changes and respond to them timely. New techniques of circulating tumor DNA (ctDNA) monitoring, as well as single-cell genomic profiling, could help us to trace ways to accomplish this complicated task.
Third, we have to consider the toxicity of new drugs and ensure that controlling cancer does not produce irreversible damage to patients’ quality of life. At present, there is a clear understanding among the clinical research community that preserving the quality of life of cancer patients presents is if not most important, but one of the most important goals in oncology care. That also places a significant burden on the pharmaceutical industry to develop effective drugs which will not be agents of destruction of patients’ quality of life.
Navigating the Academic Landscape: Important Resources, Publishing, and the Peer Review Process
As an accomplished author in the academic community, how do you see the connection between academia, science, and culture in promoting medical advancements?
We now live in a ‘social media’ world, which seems like a Janus-like creation. On one side, social media helps us to keep in contact with each other and to distribute information worldwide almost in real time easily. On the other side, social media allow easy distribution of misinformation, false claims, and targeted partial news and everybody with a functional computer can claim to be a “researcher” without any knowledge of the research process, analytical and/or interpretational skills. That places a significant burden on the academic and scientific community. We can isolate ourselves in our scientific “bubble” and refuse to discuss issues with someone who does not have the background, experience, education, and knowledge of the scientific process or choose to engage in discussion and try to present scientific data and educate the community. Both of those approaches are double-edged swords. The first approach is comfortable but leaves the education of the community in the hands of people who are using pseudoscience to steer public opinion in their direction. In medicine, that could produce devastating effects and loss of lives. The second approach seems to be right but also carries a danger of verbal and, unfortunately, even physical attacks on members of the scientific community by those who see personal or group interest in promoting falsehood. In my opinion, the role of professional societies is crucial currently since they carry the power of the group and the recognition of scientific organizations. They must be very present in social media and spread the word of wisdom, experience, science and best practices in medicine. For young researchers, it is crucial to be present in their academic and scientific societies and promote values that young people care about.
Are there any specific conferences, journals, or resources that you find valuable for staying informed in Hematology/Oncology?
In Oncology, the main resources are publications in the New England Journal of Medicine, Journal of Clinical Oncology, Blood, and Lancet Oncology, as well as general journals in biology such as Nature, Science and Proceedings of National Academy of Sciences. I attend ASCO and American Society of Hematology (ASH) meetings every year and meetings of my community oncology group (NCORP Ann Arbor) 4 times a year and South Western Oncology Group (SWOG) twice a year. I also participate in quarterly meetings of CDCN and the yearly Patients conference on Castleman in Philadelphia. Of course, I personally participate in the annual Days of BHAAAS in BiH, either in-person or online. There are several clinical investigators meetings related to specific studies I attend.
What advice would you offer early-career researchers to navigate the publishing process successfully and ensure their work reaches the right audience?
The most important aspect of the research is the reason why the research was done. Crucial is the question the researcher asks before starting the process. It has to be clearly explained; it has to have merit, has to be based on previously published work and, in my opinion, has to have practical application. After that comes methodology, which must provide adequate tools to answer questions that researchers ask. In this preparation stage, many research studies fail to meet an adequate standard. Research methodology or a statistical model fails to answer the main research question. Methodology or statistics could be completely adequate for many other situations, but not for this specific one. That is why preparation for research is sometimes more time-consuming and has a heavier workload than the research itself. Once research starts, it is impossible to go back.
As a reviewer and editorial board member of scientific journals, can you share your approach to the peer review process and what you consider essential qualities in a well-executed manuscript?
Again, when I review papers, the first question I have is why the research was done. If it was done just to explain certain phenomena, it still could be legitimate, but the threshold for publication is very high. However, if research was done to continue ongoing research or answer relevant clinical questions and open avenues for further research, then I move to methodology and statistics and research itself. If all those aspects conform to scientific scrutiny, then comes the analysis of the Discussion section. I personally would rarely reject a paper that has all previous parts navigated successfully, and Discussion is not to my liking. I think the reviewer’s role, in this case, is to point to shortcomings and offer a solution. I take the same approach with References. If they are not up to date or generally not satisfactory, the role of the reviewer is to provide them with relevant ones and improve the paper.
Drawing Strength from Heritage: Cultural Influence on a Medical Career and Research Journey and Cross-Country Collaborations
As someone from Bosnia and Herzegovina, how has your cultural background influenced your journey in medicine and research?
I am of Bosnian-Herzegovinian and Jewish heritage. I was profoundly influenced by my teachers, particularly two exceptional pharmacologists, Prof. Seid Hukovic and Prof. Vladislav Varagic, as well as my mentors Prof. Muhidin Hamamdzic and Prof. Muzafer Mujic. They instilled in me a passion for scientific research that can never be extinguished. My American journey placed me in the pathways of a giant of science, Prof. Andrew V. Schally and my teacher and friend, Prof. Maurie Markman. There were many more in my life, and some, like Prof. Momir Macanovic, have unfortunately passed away early, but they left an everlasting impression on my life and career. Culturally, I think the most influential was the Bosnian spirit of giving and helping, which was present throughout all my carrier and was crucial in the decision to practice oncology. That goes hand in hand with the Jewish tradition of Tzedakah, which in Hebrew means “righteousness”, but is commonly used to signify charity. My Jewish heritage was very important in my research because the written word in Jewish religion and tradition has almost divine meaning. That gave birth to the analytical dissection of religious texts, which corresponds almost perfectly with scientific methods.
Can you discuss your role in the National Academy of Arts and Sciences in Bosnia and Herzegovina (ANUBiH) and how it complements your work in the medical field?
The National Academy of Arts and Sciences in Bosnia and Herzegovina (ANUBiH) plays a significant role as a historical institution of immense importance, carrying the torch of science in the country. I carry a membership of ANUBiH with great pride. My role is to promote scientific knowledge as a member of the Editorial Board and Acta Medica Academica, the medical Journal of ANUBiH, as well as through presentation at Academy and participation at Academy meetings. Additionally, part of my role is to promote ANUBiH whenever and wherever I participate in national and international meetings, as I represent not only myself, but also the institutions to which I belong. I sincerely hope for ANUBiH to grow as the most influential scientific institution in the BiH and, despite resistance, continue bringing scientific advancement to every part of our country.
Have you been able to apply any of your findings or treatments in Bosnia and Herzegovina or collaborated with any institutions/physicians there?
I have several very good collaborators and friends among oncologists in BiH. We communicate frequently and discuss cases that present challenges for me or them. I offered and still offer a place in my institution for visits and clinical experience. I understand that financial issues are an obstacle, but I hope soon we can open that channel of communication. We have been discussing for some time ways to establish a tumor registry in BiH, and it seems that local oncologists are making strides. I participated remotely in meetings of local societies and will continue doing that. I receive a number of requests for additional opinions from people I know and from some I do not, which I see as a great privilege. I strive to provide help as much as I can.
You are involved with the Bosnian-Herzegovinian American Academy of Arts and Sciences (BHAAAS). Could you share more about your role within this organization and how it contributes to your work in the medical field?
When BHAAAS was founded, our primary goal was to establish a bridge for knowledge transfer between the two countries. After almost 15 years, I think that is built. Currently, the membership of BHAAAS includes hundreds of eminent researchers, doctors, and professors from the US, Canada, and BiH. These individuals work collectively to elevate scientific and medical practices, thereby improving the lives of people in BiH. I am a past President of BHAAAS and have been a continuous member of the organization’s board. Working with BHAAAS has undoubtedly helped me reconnect with my beloved homeland, a connection that I felt lost after the death of my parents.
Life Beyond Medicine: Hobbies and Interests Outside Oncology and Advice to Aspiring Oncologists
In your experience, what are the key opportunities and challenges in fostering collaborations between scientists from different regions and backgrounds?
The main obstacles and, at the same time, main opportunities are people and their cultures. Scientific communities, by definition, should be open to collaboration, without which science cannot advance. Here in the US, there is an enormous push to break down the silos that the scientific community has traditionally formed over time. Geographical distance and cultural differences make these silos in international collaboration even more challenging to break down. Advances in communication technology, enabling easier online contact, should help us communicate more effectively and establish new connections between different locations.
What activities or hobbies do you engage in during your free time to unwind? How do these activities complement your work in the field of oncology?
My hobbies are my grandchildren and European football. I am a lifelong “pitar” and lifelong Gunner. Football fans will know how to decipher that. I go to every Michigan State basketball game and am a big Spartan fan. Honestly, even on weekends, I feel guilty if I do not read at least one scientific paper a day. Prof. Varagic taught me “Nulla dies sine linea”, which in my translation, means no day without reading a scientific paper.
What advice would you give to newcomers in this field?
The same thing that I told my youngest daughter’s medical school colleagues. If you do not have a passion for helping patients who need help the most, please find something else. It is very hard, many of your patients will die on your watch, but I can guarantee you that every night when you go to bed, you will know that you made the world a better place. In addition, there is no discipline in medicine that is going through such seismic changes as oncology, and that is very exciting.