NEXT GENERATION SEQUENCINGGENOMICS

With advances in genomic technology, precision medicine continues to gain traction in oncology. Developing a structured approach for navigating Charlotte's web of cancerous pathways allows precision medicine to maximize the potential of targeted drugs by setting a firm foundation through clear illustration of the biological dynamics.

Ravi Dashnamoorthy Senior Scientist, Genosco

1. It seems like genomic sequencing is getting more attention. What distinguishes genomic sequencing from conventional cancer genetic testing?

The genomic sequencing approach allows for a comprehensive analysis of human DNA for gene sequence changes, enabling the detection of cancer associated novel genetic changes in unexpected genes. Conversely, cancer genetic testing is oriented toward preselected target genes, generally chosen by family history, inheritance and susceptibility risk. Further, with less than 10% of cancers being inheritable, genetic testing may miss identifying cancers that are not inheritable, which make up the majority of all cancers. Most importantly, genomic sequencing provides a means of identifying potential drug targets and allows physicians to prescribe precision medicine and facilitate providing personalized treatment. Finally, with the completion of the human genome map and the availability of affordable sequencing technology, genomic sequencing is becoming an increasingly acceptable diagnostic tool.

2. Why do you think we are seeing an increase in the demand for genetic data in clinical development?

Cancer treatment was traditionally dominated by treatments such as chemotherapy, radiation, and surgery until the early part of this century. In the United States and around the world, these treatments continue to be the firstline option for many types of cancer. In recent years, genomic sequencing has enabled the discovery of novel targets and the development of targeted drugs that match these targets. This has resulted in improved treatment efficacy and a reduction in side effects. These newly developed targeted drugs were also formulated for oral consumption, making them very attractive options for patients who wish to reduce the frequency of hospital visits. Consequently, healthcare providers who opt to provide personalized care with tailored therapy began integrating genetic abnormalities into their treatment decision-making processes. As a result, genetic datasets are in high demand in the healthcare sector.

3. Could you explain precision oncology's full range of applications and how they affect clinical outcomes?

The treatment outcome of patients with the same type of cancer tends to vary widely from patient to patient; this has remained a challenge that is biologically unresolved. Through precision oncology powered by genomics, new molecular subtypes have been identified, allowing for improved disease stratification, more accurate patient selection for clinical trials, and providing better personalized treatment. Because targeted therapeutics aim to inhibit the biological activity of key genetic drivers of the disease, administering these treatments results in better clinical outcomes. As a result of improved outcomes, healthcare providers are also able to grow profitably. Overall, precision oncology is becoming a crucial part of diagnostics, drug discovery, and development, enabling clinical trials and facilitating treatment decisions.

4. Is there any particular genomic development that you find fascinating at the moment?

The use of spatiotemporal resolution, single-cell RNA sequencing platforms provides a fascinating new insight into the microenvironment of cancerous tissues containing different types of cells. Targeted therapeutics, whether small molecules, biologics, or cell-based therapies, require a thorough understanding of the biological background of the disease. This is in part due to the fact that some drugs target cancerous cells whereas others work indirectly through normal cells located in the vicinity. It is also imperative to note that cancer is intrinsically a biologically complex disease. Thus, such technologies provide precision medicine with a better basis for providing personalized treatment by resolving the complexities of these diseases. Oxford Nanopore is another exciting development in genomics, which is a pocket-sized, affordable, portable sequencing system that can be used by anyone anywhere without requiring any technical skills or training. This platform can be effectively integrated into any small healthcare facility without a significant investment in capital, and eventually could evolve into a useful tool appropriate for self-diagnosis at home.

5. Could you explain the Abacus Strategy and how it is applied to genomics?

The conventional wisdom holds that genetic changes are unpredictable and random. Genetic changes can be inherited (germline, which is passed from parent to child) or acquired (somatic, which is not associated with reproduction). If the changes are consequential, germline and somatic genomic changes can cause cancer. These genetic and biological changes are dynamic and evolve with disease progression, which presents a significant challenge for precision medicine applications. In essence, these changes in genomic and biological dynamics mimic the "Charlotte's Web" effect, which enables cancer cells to evade the therapeutic effects of a drug intended to block a key biological regulator associated with malignancy by redistributing the control to a different biological factor. For this reason, predicting cancer's next genetic move is an effective method for developing smart strategies to prevent cancer progression. We therefore, developed an Abacus strategy based on primitive learning to convert RNA sequencing datasets into linear biological paths, then overlay genomic data to predict genetic changes over time, published in Biomedicines 2022, 10(11), 2720; doi. org/10.3390/biomedicines10112720. As a result of this research, a systematic method has been developed to construct biological GPS maps of cancer progression patterns. This will eventually allow us to predict future biological states and genetic changes associated with cancer.

6. How would you rank the USA's competitiveness given the global boom in the genomics industry?

As a nation that has sequenced the entire human genome, developed and introduced several sequencing platforms, integrated artificial intelligence into genomics, incorporated genomics into clinical and translational research, and facilitated the discovery of many new drugs, the USA has always been a leader in genomics, ranked number one in this field.

7. The promise of genomics for personalized and preventative medicine has lagged behind, according to several experts. What obstacles do you observe?

There is no doubt that genomics has fallen short of expectations when it comes to the development of personalized and preventive medicine. The former US president Barack Obama expressed frustration about the slow advancement of genomics in medicine. According to him, the healthcare system isn't keeping up. In reality, it's different. The results of several highly-profile genomicsguided precision medicine trials (SHIVA, MOSCATO-01, Copenhagen Prospective Personalized Oncology (CoPPO), MAST, PERMED 01, PREDICT, etc.,) indicate that only 10% of patients improved their progression-free survival through drug-target matching. As a result, precision medicine fails to help many cancer patients. Integration of genomics into healthcarehas several obstacles. The process of making therapeutic recommendations based on genomic data is complex. Physicians may be hesitant to accept target-drug match recommendations based on genomic analysis. Precision medicine cannot be established without understanding the biological mind of cancer. We also do not have the ability to create drug combination cocktails based on patient biology instantly, nor do we have access to matching drugs for many actionable targets. Implementing the proper framework by integrating biology and dynamics, defining guidelines for conducting clinical genomics investigations, ensuring data security, creating a database of clinical experiences using target-drug matching treatments, integrating intelligent decisionmaking algorithms and establishing principles and practices for precision medicine all these are necessary to ensure patient and oncologist confidence.

8. What would you say about the state of translational research in the USA, especially in oncology?

Translational research aims to turn bench research into clinical practice at the bedside. Academic centers and hospitals are utilizing advances in genomic research to foster research activities. This is done through the establishment of clinical and translational research institutes for training and attracting grant funding from government organizations and private sources. These initiatives have been widely adopted in the United States, which is certainly commendable. Academic institutions primarily provide seed funding so that investigators can secure larger grant funding, thereby allowing them to realize significant benefits from indirect costs, several successful start-ups, enabling academic-industry collaborations grew out of such initiatives. More emphasis must be placed on identifying and solving unmet needs in the local community, and visionary leadership is essential to develop and grow and establish a long-term research resources that will benefit patients in the long run. Recent debate suggesting that cancer arises from bad luck rather than genetic changes (Source: Scientific American, March 2017 and other outlets) not only confuses the public, but also suggests that our understanding of cancer biology is incomplete. Translating oncologists are responsible for ensuring that the biological foundations for the understanding of cancer and its nature are solidly established. If translational oncology research adopts the rocket science mentality of tackling and achieving a single mission, single goal attitude, it may be able to achieve remarkable results for every cancer.

9. What do you think the future of biomarkers is?

Biomarkers are rapidly gaining in popularity as non-invasive diagnostic tools. As an example, colon cancer can now be detected through DNA analysis of stool specimens, eliminating the need for uncomfortable colonoscopies. It is becoming more common to perform liquid biopsies, as the sequence of circulating tumors and tumorderived materials from blood is becoming a valuable tool for detecting cancer early, tracking prognosis, and tracking recurrence. Simplicifying sequencing will lead to faster biomarker assessment and will enable at-home "glucometer-like" systems with smart technology and AI. Biopsies of tumors are ideal specimens for the assessment of biomarkers, however, repeat biopsies from the same patient may not be possible. Additionally, for certain types of cancer, biopsies may be difficult to obtain due to anatomical limitations, making liquid biopsies the only option for planning any precision medicine therapy.

10. What are the most serious issues that cancer patients in the US are currently facing?

There is limited access to advanced cancer therapies. Therefore, patients must either accept what is locally available or may be required to travel a long distance or across states to receive such treatment. The cost of cancer treatment is skyrocketing, and patients without access to comprehensive health insurance suffer the most from physical, mental, and financial hardships. In some cases, patients who have exhausted all other options, financially broke resort to risky unproven alternates in the hope of a miracle. In the case of uneducated or low-income individuals, disease awareness, treatment options, and the importance of follow-up are relatively low, and some people do not seek medical help until the disease becomes terminal. Celebrities, community leaders, and foundations can play a significant role in bringing awareness and providing guidance regarding cancer to the community.

11. What innovations do you anticipate taking place in the next 12 or 5 years?

During the next decade, genomic sequencing will be an affordable, simple and user-friendly diagnostic tool that will be seamlessly integrated into clinical settings. As a result of the success of the mRNA-based COVID vaccines, a mRNA-based cancer vaccine will be developed based on targets derived from genomics. Genomic sequencing is utilized to assess tumor mutation burden for cellbased immunotherapy, the presence of tumor reactive immune cells, and therapeutic immune cells, such as CAR-T cells. Increasing FDA approvals for immunotherapy and targeted therapy will lead to the development and marketing of targeted genetic screening with digital PCR and portable next generation sequencing platforms, ultrafast innovative biosensor chips, digital wearables or stripbased detection kits along with AI integration will be the future.

The "omics era" presents us with unprecedented opportunities for scientific advancement because of our ability to integrate assessments from genomics (DNA), transcriptomics (transcriptomics), protein (proteomics), and metabolomics (metabolites derived from biochemical reactions). The development of fundamental knowledge, early detection, diagnosis, prediction of prognosis, and drug discovery and development have enabled newer approaches to arriving at treatment decisions that provide unparalleled opportunities. In recent years, advancements have already resulted in a reduction in cancer death rates, but much remains to be done. The incidence of cancer is on the rise worldwide, and the number of cases and deaths are expected to nearly double by 2040. Increased healthcare costs and inadequate expansion will lead to an unimaginable tragedy. As a comparison, COVID killed 6.6 million people in 3 years, while cancer kills 9.96 million each year. With an estimated 30 million new cases per year by 2040, 17 million people will die from the disease. In the absence of quick action, our entire world will face far reaching misery worse than COVID. Public-private partnerships that promote science advocacy, establish a basic science foundation, raise awareness, invest in technology and drug development, share genomic data and experience from precision therapeutics, and increase intellectual cooperation, although they are already present, require more intensified efforts to strengthen our fight against cancer.

AUTHOR BIO

Ravi Dashnamoorthy is a Ph.D cancer biologist who studies molecular pathways of cancer progression. As a Senior Scientist at Genosco, Billerica, MA, with 25 years of academic research experience, published 40+ articles and 75+ abstracts in basic and translational oncology. Genosco is a clinical stage biotech company specializing in discovering novel kinase inhibitors for patients with unmet medical needs.