My journey in healthcare, starting with a PhD in molecular cell biology focusing on cancer, led to a career shift during my postdoctoral fellowship at Yale. I became the first employee of a molecular diagnostics startup, transitioning from molecular carcinogenesis to clinical microbiology. Over three years, I developed clinical assays for antibiotic resistance and managed a genomics division. These experiences prepared me for Cancer Genetics Inc.'s goals in India, focusing on next-generation sequencing (NGS) for personalized cancer diagnostics. NGS technology enhanced our ability to analyze genetic aberrations comprehensively, solidifying our role in personalized cancer care.
1. You’ve had a long run with the healthcare industry, during the course of which you must have accrued boundless acumen. Kindly highlight some of the milestones of your career’s journey.
As a graduate student pursuing a PhD in molecular cell biology, with a focus on cancer initiation and progression, I realized that my heart lies at the forefront of applying my skills to experience a more direct impact on patient care.
The amorphous desire evolved into a career path towards the end of my postdoctoral fellowship at Yale, where my then PI founded a molecular diagnostics company, albeit in the field of mass spectrometry and clinical microbiology.
Becoming the first employee of such a start-up required that I firstly alienate the field of molecular carcinogenesis and begin exploring a new field and secondly, begin balancing scientific discovery with business development. Then again, after three years of successfully developing a clinical assay for rapid detection of antibiotic resistance, I changed fields and began managing a genomics plus bioinformatics division of a Next Generation Sequencing (NGS), microarray and bioinformatics service provider without a specific focus on any disease.
This allowed me to identify the capabilities of the NGS technology and prompted me to think about how we could utilize NGS for effective translation of genomic discoveries. All three tenures i.e. classical cancer biology, diagnostic test development, and NGS and bioinformatics were a perfect combination for what Cancer Genetics wishes to accomplish in India.
I think starting afresh every few years has broadened my skill set, kept my mind open and allows me to be comfortable with a rapidly changing biotechnological landscape.
2. How did the idea of delivering 'personalised medicine' gain momentum at Cancer Genetics Inc.?
Cancer Genetics has always focused on translating cancer related genetic discoveries into diagnostic tests. We have had success in bringing many fluorescence in situ hybridization (FISH), immunohistochemistry, fluorescence activated cell sorting (FACS), and PCR based cancer diagnostic tests to the market. Improved understanding of the contribution of multiple genetic aberrations to cancer initiation and progression prompted Cancer Genetics to adopt a more comprehensive platform capable of identifying several genetic aberrations in a single test.
Owing to its ability to simultaneously detect many mutations/variants, high sensitivity and specificity, and declining cost makes NGS a great platform for Cancer Genetics, which has been technology-agnostic and expects to become a leading bench-to-bedside partner for improved and personalized cancer diagnostics.
3. For many, DNA-based cancer diagnostics is just a game of technology. How does it pave way for precision medicine in Oncology?
Today, DNA-based cancer diagnostics is a reality for many cancers, for example, detecting BCR:ABL from a patient with CML directly impacts clinical management. Over the last 20 years, we have come to appreciate that cancer is a genetic disease driven by a combination of several mutations in different genes, while the set of genes and type of mutations found in the same cancer type from two individuals can be different and unique for each patient.
Often, a subset of these mutations, known as ‘driver’ mutations, are responsible for fuelling the uncontrolled growth of the tumour and are indicative of the aggressiveness of the cancer. In certain myeloid malignancies (e.g. MDS, MPN, and AML), available clinical tests are unable to distinguish between the cancer subtype. Moreover, we continue to develop several therapeutic molecules that target specific genetic changes in cancer and the efficacy of such drugs depends on the presence of the targeted underlying mutation.
Therefore, accurate identification of the collection of mutations found in an individual patient’s tumour enhances diagnosis, improves prognostication, and guides therapeutic choice. This is at the core of precision medicine in oncology. NGS has ushered in a new era of detecting many DNA variations from a single sample in a single protocol, which is perfect for accurate molecular typing/diagnosis, prognosis, and theranosis. I think NGS was a game of technologies 10-12 years ago and it has already transformed the way we detect genetic variations from biological samples. It will continue to evolve into a more powerful, cost effective, and easy-to-use technology but precision oncology is one of the most significant applications of NGS. It relies on 1) detecting the set of mutations found in a clinical sample and 2) carefully analyzing the impact of the specific set of such mutations on the individual’s life.
As we learn more about the genetic variation in each cancer, the tests will be enhanced and empower the physician with more clinically relevant actionable information.
4. What are the current technologies and applications associated with next-generation sequencing?
Low data throughput, which is the major shortcoming of the previously popular DNA sequencing technology, became the driving force for the development of NGS that sequences millions of DNA fragments in parallel to generate large DNA sequencing datasets.
The primary difference between different NGS platforms is the chemistry/method of detecting the DNA sequence, which in turn dictates their utility for different applications of NGS. The power of NGS is to indiscriminately sequence all the DNA fragments “loaded” into the sequencer. Although whole genomes from each sample can be sequenced, it is neither cost effective nor useful to always do so. On the other hand, it is very useful to sequence the subset of DNA fragments that are directly relevant to the goal of each experiment/test. This means that applications of NGS are bound only by how you select the DNA fragments of interest from the whole genome. For example, you can select and sequence only a small set of genes or only the “coding regions” of all genes or only the expressed RNAs or only the genes present in the mitochondria etc.
Based on the DNA (or RNA) that is selected for sequencing following are a few applications of NGS, whole genome sequencing, whole exome sequencing, targeted sequencing (panel sequencing), mRNA sequencing, small RNA sequencing, metagenome/microbiome sequencing etc.
For precision oncology, targeted sequencing of a collection of genes relevant to the particular cancer is a major focus for Cancer Genetics and we develop cancer-specific panels for optimizing diagnosis, prognosis, and theranosis of cancer.
5. There’s an emerging norm that ‘liquid biopsy’ is driving the investment opportunities for diagnostic companies, what’s your view on this?
Liquid biopsy is certainly one of the most exciting and promising technique that may have a significant impact on how we obtain clinical samples for cancer diagnosis. It promises to overcome several challenges of conventional biopsy and fine-needle aspiration cytology, such as capturing tumour heterogeneity, ease of collecting serial samples for the assessment of accumulating changes in tumour DNA (disease progression), regular monitoring of disease remission etc.
Currently, significant effort is focused on addressing the major challenge of the sensitivity of liquid biopsy. Importantly, finding circulating tumour cells (CTCs) or cell-free DNA (cfDNA) from liquid biopsy samples at a level that accurately reflects disease state will rely on NGS.
6. Cancer Genetics Inc. works with biotech and bio pharmaceutical companies. How does the support and engagement transform cancer patient management?
In addition to developing cancer diagnostic tests, support to biotech and pharmaceutical companies is not restricted to a specific technology and involves several areas. They can be broadly categorized into:
1) Development of genomic assays in support of discovery and/or validation of a set of genomic changes observed in the disease under investigation
2) Development of companion diagnostic assays that enable screening of patients prior to choosing targeted therapy
3) Development of assays that enable genetically guided inclusion-exclusion criteria for increased success rate of clinical trials
4) Development of assays that can predict the pharmacogenomic interactions of a new chemical entity.
Some of these assays have a more direct impact on patient care e.g. the PD-L1 companion diagnostic assay developed by Cancer Genetics Inc. directly assists in the choice of PD-L1 inhibitor regimen for clinical management of certain cancers.
Overall, most assays that we develop help us develop a deeper understanding of the genomics of cancer, provide accurate clinical information about cancer, and improve translation of cancer-related discoveries into tangible and clinically actionable information for better managed cancer care.
7. As the Chief Technology Officer of Cancer Genetics Inc., how do you think the prospective projects of your organisation will impact the lives of low income earners?
As a global organization operating in a developing country such as India, we are highly cognizant of the market behaviour. Several aspects of genomic testing lower the overall cost of the clinical management of cancer. Firstly, the upfront increase in cost due to testing can significantly lower the total cost of therapy because the testing is expected to optimize the drug choice and regimen.
Secondly, monitoring of the disease at regular intervals may further reflect the effectiveness of the therapy and provide realistic clinical insight about outcome. Thirdly, NGS based tests allow for detecting several variants in parallel, which saves valuable time that may otherwise be lost if single gene variants are tested in series. Fourthly, there are non-NGS tests that address high incidence of cervical cancer i.e. FHACT, which is a FISH based test used as an effective secondary screening of women with abnormal pap smears.
Lastly, there are a few novel projects that rely on NGS in the discovery phase but may not translate into an NGS-based clinical test. We will explore multiple possibilities that will cater to lowering the cancer burden on low income households.
8. With more organizations adopting patient-centric cancer treatment, what could the development of oncology-focused knowledge base mean?
An oncology-focused knowledge base feeds directly into clinical interpretation of any test that detects genetic variants in cancer samples. Incidence and association of specific variants with particular cancers aids in increasing the accuracy of diagnosis, prognosis, and theranosis.
Several such highly informative knowledge bases have been developed and continue to be updated with new information. Unfortunately, India has not focused on this effort so far. Over several years, we have learned that the epidemiology and etiology of cancer differs with ethnicity, which needs to be captured through indigenous knowledge bases for clinical reporting in the Indian context.
Such knowledge bases should be well designed, meticulously catalogued, regularly updated, and available in the public domain for the greater good of cancer patients.
