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Targeting Biomarkers for Tissue-Agnostic Therapies for Cancer Treatment

Heather Brown
Tags: Cancer,

  • Large-scale tumor sequencing efforts revealed that many cancers are driven by the same genetic aberration, regardless of tissue of origin.
  • Tissue-agnostic therapies are anti-cancer treatments that target a common genetic biomarker of cancer regardless of the tissue. This method has shown promising results in treating various cancers driven by a shared genetic biomarker.
  • While tissue-agnostic therapies cannot replace traditional diagnostic/treatment methods, they can provide another mechanism to treat and cure cancers with a causal biomarker. Clinical trials are currently in progress to approve new tissue-agnostic therapies.



Cancer Defined:

The human body begins as a single zygotic cell, which grows, proliferates, and differentiates into a collection of distinct and diverse cell types. Differentiation and proliferation of these stem-like cells into their fated cell type are driven by changes in gene expression and a myriad of signaling cascades that steer a cell to their fate, such as a skin cell, or a liver cell. Since virtually every cell in a human body contains the same genome, how does a cell know which genes to express at which times? How do they know when to stop dividing? What happens when these processes are disrupted? Understanding these fundamental questions about cell biology is paramount to understanding human pathologies, specifically cancer. Cancer refers to diseases in which abnormal cells divide out of control and are able to invade other tissues (1). In the US alone, cancer was the second leading cause of death in 2020. Globally, new cancer cases reached 19.3 million, and deaths reached nearly 10 million in 2020 (2). There are many causes of cancer, such as genetic mutations, environmental carcinogens, alcohol/tobacco use, sun exposure, viral infections, and even diet and exercise habits (3). Given the complex relationship between the genetic and environmental insults that cause cancer, it can be unpredictable and difficult to treat. Despite best efforts, further study and scientific breakthroughs in cancer research/treatment are required, evidenced by the hundreds of thousands of people still dying from cancer every year.


Current Cancer Treatments:

According to the National Cancer Institute, US costs for cancer care were estimated to be $190.2 billion in 2015 and increased to $208.9 billion in 2020 (4). This financial burden is an obstacle that inhibits many from getting the care they need. Furthermore, some patients receive expensive treatments, yet they are ineffective and unable to stop cancer growth. Not only does this financial burden harm patients and families involved, it also strains the healthcare budgets and the economy as a whole. Therefore, advancements in cost-effective and successful treatments are imperative to create a healthier future. Traditionally, oncologists have treated patients based on the organ or tissue where the tumors originated (i.e., breast cancer treatment, lung cancer treatment, etc.). These treatments include surgery, radiation, chemotherapy, hormone therapy, immunotherapy, targeted therapy/local therapy, and can be deployed alone or in combination. However, growing research and patient data show that treating cancer based on its tissue of origin may not be the most effective way to eliminate cancer. Instead, cancer is now being treated based on the genetic markers present in the tumor, regardless of the tissue it occupies. This approach, termed “tissue-agnostic” therapy, targets specific genetic biomarkers that occur across various cancers/tumor sites to treat a greater variety of cancers with a single targeted treatment (5).


Tissue-Agnostic Therapy and the Genetics of Cancer:

The advent of next-generation sequencing (NGS) has allowed large-scale tumor sequencing projects that have revealed several genomic markers that drive cancer growth and progression. For example, mutations in the EGFR (Epidermal growth factor receptor) gene are present in various metastatic cancers such as Non-Small Cell Lung Carcinoma (NSCLC) and have since become a target for tissue-agnostic therapy. EGFR encodes for the EGFR protein, a cell surface protein that binds to epidermal growth factors to induce cell proliferation. In fact, S. Rao et al. (2015) used Enzo’s native EGF Receptor to show that inhibition of EGFR results in decreased proliferation and invasion of cancer cells (6). Furthermore, RAF (Proto-Oncogene, Serine/Threonine Kinase) mutations are strongly associated with melanoma, NSCLC, colon cancer, thyroid cancer, multiple myeloma, glioma, and pancreatic cancer. The encoded protein is vital for initiating phosphorylation events that regulate cell division, apoptosis, cell differentiation, and cell migration. Not only are novel genetic biomarkers being revealed via sequencing approaches, but new cancers are being associated with previously known genetic biomarkers. For example, HER2 mutations are known to be present in breast cancers. However, since the implementation of high-throughput genetic sequencing, HER2 mutations are now associated with esophago-gastric cancer, bladder cancer, and endometrial cancer (7). These genetic biomarkers across many types of cancer provide a platform to develop and implement tissue-agnostic therapies to treat a myriad of cancers. This technique will capture genetic variation from one patient to the next and allow the therapy to target the patient-specific biomarkers to improve outcomes.


Examples of Tissue-Agnostic Therapies:

Tissue-agnostic cancer therapies are drugs that treat cancers based on the mutations that they display instead of the tissue type in which they appear. Therefore, tumor-agnostic treatment can treat any cancer as long as the tumor has the specific genetic alteration targeted by the drug. A cellular process that current tissue-agnostic treatments target includes immune checkpoint inhibition. The first FDA-approved cancer therapy targeting immune checkpoint inhibition regardless of tumor location is Pembrolizumab (Keytruda®). This immunotherapy targets PD-1 (programmed cell death receptor-1). Typically, one’s T cells are activated by the adaptive immune system to detect infections/pathogens destroying the pathogenic cell (such as a cancer cell), cytokine production, and increased T cell production to continue to fight the biological threat. During the immune response, PD-1 is turned on to protect “self” cells from destruction, working as a negative regulator of the immune system to keep healthy cells safe from immune attack. In the context of some cancers, the cancer cell hijacks this mechanism via the PD-1 pathway to turn down the immune system so that it does not recognize pathogenic cells, which then allows the cancer cells to grow and proliferate without immune detection/attack (Figure 1). Promising results obtained by D.E. Dolan et al. (2014) using Enzo’s recombinant human PD-1 protein demonstrated that anti-PD-1 agents have a good safety profile and have resulted in durable responses in a variety of cancers, including melanoma, kidney cancer, and lung cancer (8). These immuno-oncology studies and studies like it paved the way for the development of the FDA-approved drug Pembrolizumab (Keytruda®). Pembrolizumab inhibits the cancer cell from using PD-1 to bind ligands that dampen the immune system, resulting in an up-regulation of the immune system, which in turn allows T cells to identify and kill the cancer cells (Figure 1).

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Figure 1. PD-1 inhibitors such as Pembrolizumab are used for some tissue-agnostic therapies in order to increase the immune response against cancer cells. Reprinted from “Immune Checkpoint Inhibitor Against Tumor Cell”, by BioRender.com (2022). Retrieved from https://app.biorender.com/biorender-templates.


Another example of a tissue agnostic immunotherapy is Larotrectinib (Vitrakvi®). This therapy targets aberrant molecular pathways resulting from NTRK (neurotrophin receptor tyrosine kinase) gene fusions. In NTRK positive cancers, any of the NTRK genes (NTRK1, NTRLK2, NTRK3) becomes inappropriately fused with another gene, resulting in cancer progression. In a healthy individual, the NTRK genes produce proteins that regulate the growth and proliferation of neuronal cell types. However, when it becomes fused with another gene into a fusion oncogene, it results in the production of carcinogenic fusion proteins that drive cancer growth and progression. These genetic fusions are typically diagnosed using FISH techniques. Larotrectinib (Vitrakvi®) inhibits the production of these proteins, effectively slowing the progression of cancers with this genetic biomarker.

Additional tissue agnostic immunotherapies are approved for different indications, and there are currently dozens more tissue-agnostic treatments in clinical trials. The main clinical trials for tissue agnostic therapies are the MATCH and TAPUR trials. These trials enroll patients based on their genetic biomarkers, regardless of the tumor origin. This clinical trial method is called a “basket trial” (Figure 2). There is much hope that these agnostic therapies will continue to show efficacy in defeating many types of cancers when previous treatments were ineffective.



Figure 2. Schematic representation of basket clinical trials. Patients are grouped based on the genetic driver of cancer, regardless of the tumor's tissue of origin. Figure created using BioRender.com.


Continued Studies and Future Directions for Tissue Agnostic Therapies:



While tissue-agnostic therapies show great promise to treat previously untreatable cancers, continued research is required to advance our understanding and awareness of the genetic biomarkers that drive cancer. For example, most cancers are not driven by single genetic mutations; they are derived from a complex interplay between genomic, transcriptomic, and proteomic alterations as well as the tumor microenvironment and immune system abnormalities (9). Moreover, it is imperative to resolve which mutations are driving cancer phenotypes and which mutations are not. Identifying this has implications for what is used as control sequences when comparing patient samples or detecting novel cancer causing mutations. Similarly, matched non-malignant DNA from a patient can serve as a control to help distinguish somatic mutations from inherited germline variants to more specifically characterize cancers (7). Genetic panels are currently used to detect recurrent actionable mutations such as EGFR, NTRK, RAF, and HER2. However, not all genetically driven cancers will be identified with this method, exposing the great need for continued studies. Finally, access to these therapies and their reimbursement by insurance companies is often limited in patients without standard IHC diagnostics.

Tissue-agnostic therapies cannot completely replace traditional testing and diagnostic methods since there is still so much to learn. For instance, patients with metastatic cancers can develop acquired resistance following prolonged treatment with tissue-agnostic targeted therapy. This is because the cancer cells hijack another cellular pathway to avoid the pathway being targeted by the treatment. This immune evasion needs to be understood in order to design treatments that prevent this. Therefore, we can build upon our current knowledge of genetic biomarkers of cancer and continue to search for new ones via NGS, array CGH, ISH/FISH, coupled with traditional IHC analysis. A multi-faceted approach to understanding the genetic diversity of cancer will help develop individualized treatment plans that account for the variation and unpredictability of cancer, resulting in more cures.


Are you studying tissue-agnostic therapies for cancer treatment? Let Enzo help you reach your goals and reach out to one of our application scientists today!
 

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References:

  1. Cancer | Center for Disease Control (link)
  2. H. Sung, et al. (2021) Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 71, 209. Abstract.
  3. What causes cancer? | American Cancer Society (link)
  4. Financial burden of cancer car | National Cancer Institute (link)
  5. The surge of oncologic tissue-agnostic therapies: a precision medicine maneuver | IQVIA (link)
  6. S. Rao, et al. (2015) Target modulation by a kinase inhibitor engineered to induce a tandem blockade of the epidermal growth factor receptor (EGFR) and c-Src: the concept of type III combi-targeting. PLoS One. 10, e0117215. Abstract.
  7. M.F. Berger, et al. (2018) The emerging clinical relevance of genomics in cancer medicine. Nat Rev Clin Oncol. 15, 353. Abstract.
  8. D.E. Dolan, et al. (2014) PD-1 pathway inhibitors: changing the landscape of cancer immunotherapy. Cancer Control. 21, 231. Abstract.
  9. J.J. Adashek, et al. (2021) From tissue-agnostic to n-of-one therapies: (R)Evolution of the precision paradigm. Trends Cancer. 7, 15. Abstract.

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