By Germaine Cornelissen-Guillaume
This is a beautifully written book by Dr. Azra Raza, an oncologist specializing in the treatment of myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). It consists of detailed stories of several of her cancer patients, eloquently and emotionally narrated and interspersed with English and Arabic poetry, blended with scientific discourses on the fight against cancer. The tenet of the book revolves around the question whether more efforts should be redirected toward killing cancer cells at their inception instead of pursuing the elusive goal of killing the last cancer cell.
Raza decries the status quo where surgery, chemotherapy, and radiation have remained for the most part unchanged in decades as the standard slash-poison-burn approach to treating cancer. She makes the case that, at great cost, the 72 anticancer drugs newly approved by the FDA between 2002 and 2014 only prolonged survival by 2.1 months on average, and that 30 to 70% of the approved drugs may actually be harmful to patients. Of the two approved strategies to treat MDS, one drug (Revlimid) is restricted to a small subset of patients, and the two drugs (Vidaza or Dacogen) recommended to treat all other cases only have a 20% chance to improve anemia in low-risk MDS patients enough so that they would no longer need transfusions. Two major issues are that it is not currently possible to identify those patients who will respond to treatment and that those patients who respond to treatment are not cured, their response duration averaging about 10 months.
The author attributes this dismal situation to the fact that cancer is not a static disease but a highly heterogeneous and continually evolving process, from initiation to progression, invasion, and lethality of the disease. She argues that animal models and test tubes where cancer cells are artificially maintained should not serve for the development of oncostatic drugs because they lack the complexity of human cancers. Another reason for the poor performance of drug development is the fact that as many as two thirds of them are approved based on surrogate endpoints and not directly on improved survival.
The goal of identifying predictive markers and finding a mutation by sequencing the DNA of the patient’s cancer cells in order to individualize treatment by matching drugs to patients may sound like a good idea. In reality, however, one gene usually does not drive one cancer; even when such a mutation is identified, there may not be any effective approved targeted treatment for it; and even when there is one, the patient’s response remains both uncertain and limited in its duration.
Raza points out that gains made in the fight against cancer during the past 30 years or so are largely due to the institution of preventive measures, such as the promotion of smoking cessation, screening for colorectal cancer, and early detection of cervical cancer by means of Pap smears. The prevention avenue followed in her own research consists of the identification and eradication of transformed cancerous cells at their inception, before they can organize into a malignant, incurable cancer. She advocates the use of “liquid biopsies” to look for early biomarkers of malignancy in bodily fluids, such as somatic DNA driver mutations, epigenetic changes, cancer-specific RNA and proteins, cancer-specific metabolites in the plasma, sputum, urine, and stools, while also employing molecular imaging techniques. She envisions the combination of emergent groundbreaking technologies in multidisciplinary areas between geneticists, biomedical engineers, radiologists, oncologists, molecular biologists, nanotechnologists, AI experts, computer scientists, and bioinformatics wizards to monitor a host of variables to look for early alterations pinpointing the presence of the first few cancer cells.
While this may still be a pie in the sky, the author has taken a pragmatic first step in building a tissue repository, a collection of sequential samples from her patients throughout the evolution of their disease, backed by a computerized data bank containing detailed clinical and pathologic information on each patient. By interrogating the data using new technologies encompassing genomics, transcriptomes, proteomics, and metabolomics once the fate of the patients is known, new light can be shed on how MDS may develop into AML in some patients and who are the patients responding to a given treatment. Raza hopes that identifying and targeting the first leukemia cell will become possible once important biomarkers of leukemia cells emerge through this high-throughput technology. As described in the book, her approach has already led to new therapeutic modalities by realizing that, contrary to previous assumptions, the bone marrow cells in MDS patients are hyperproliferative, and that the low blood counts result from premature death of the clonal cells by apoptosis, mediated in part by the pro-inflammatory proteins TNF and TGF. Thalidomide with anti-TNF effects produced complete responses in 20% of MDS patients, while Revlimid and Luspatercept have shown activity in MDS by inhibiting the TGF family of proteins.
There is, however, one topic that is strikingly missing from her proposed approach, even though she named her “Therapy-Induced Malignancy Evaluation” Center “TIME” to identify MDS-susceptible individuals through twice-yearly “liquid biopsies” in patients who eventually develop MDS after being treated with chemoradiation for other cancers. Another kind of TIME should also be part of her armamentarium to fight cancer. Circadian disruption has been associated with both a higher risk of cancer diagnosis and recurrence. By doing no more than optimizing the timing of treatment, already by the 1970s, circadian chronotherapy led to cures of L1210 leukemia in mice with ara-C and to the doubling of two-year disease-free survival in patients by radiotherapy. Work at the molecular level is now showing how clock genes are intricately involved in the initiation and proliferation of different cancers. Adding the time of treatment administration as another item in large patient databases should no longer be an obstacle to including the principles of chronobiology in the fight against cancer.
For the author, the fight against MDS and AML is poignantly personal, as the condition killed her husband, Dr. Harvey Preisler, an oncologist who also specialized in AML and directed the Rush Cancer Institute in Chicago, and their daughter’s best friend, Andrew.
Germaine Cornelissen-Guillaume is a professor of integrative biology and physiology and director of the Halberg Chronobiology Center at the University of Minnesota, Twin Cities.