Cancer Sheds Undruggability Tag

For cancer to be successful, several biological pathways have to be malfunctioning. Cancer in its entirety should not be a biological certainty and yet it has evolved into the most prevalent and threatening disease globally. Every year the cancer disease burden exponentially increases, with India recording an appalling increment in the past couple years. 8.51 lakh people in India fall prey to cancer every year (International Agency for Research on Cancer, 2020, Globocan). According to the World Health Organisation (WHO), one in 10 Indians will develop cancer during their lifetime, and one in 15 will die of cancer. Adding to this challenge is the growing presence of undruggable cancer. But does this have to be the norm? Let’s find out.

Undruggable cancer refers to those cancers with protein mutations which are difficult to pharmacologically target for therapeutic purposes. In cancer, some of the disease-modifying targets are rendered “Undruggable” or “difficult to drug” because of absent features like catalytic sites, accessible drug-binding pockets, etc. that aid in viable drug designing, for example, proteins like Kirsten rat sarcoma viral oncogene (KRAS); Master Regulator of Cell Cycle Entry and Proliferative Metabolism (MYC); Tumour protein p53 (TP53); Epidermal growth factor receptor (EGFR), etc.

Nevertheless, with betterment of oncological research and cutting-edge technology, several drugs have been developed to target such proteins, making them druggable or at least capable of being combatted. However, the impediment lies in the path between ‘the lab’ and

‘the clinic’. Translational research to bridge this gap, is the need of the hour.

Dr Niti Raizada, Director - Medical Oncology and Hemato-Oncology and Transplant Physician, Fortis Hospital, Bengaluru said, “Due to the rapid pace of scientific advancement, yesterday’s “undruggable” targets are now viable new research subjects, hence terms like “tough to drug” or “still to be drugged” may be more applicable. Over the last several decades, many of the drivers, particularly kinases, have provided druggable targets that have generated major clinical advantages. However,

due to wide protein-protein interaction (PPI) interfaces or a lack of deep protein pockets, many recognised drivers such as RAS, MYC, and fusion transcription factors typically observed in pediatric malignancies, lung cancer, etc. have been deemed undruggable. As a result, drugging these intractable targets, as well as the impediments to properly understanding tumour heterogeneity and drug sensitivity and resistance mechanisms, is currently one of the major difficulties in cancer research. But a lot has changed and research has made these targets also ‘druggable’. Drugs like sotorasib are in that league. Other than small molecules, new ways are

continually appearing. New chemical techniques may offer a way to get beyond these targets’ inability to be manipulated.”

A detour around Undruggability

Proteins with quirky structures, even though difficult to target, have not demoralised scientists from attempting experimentation. The enigmatic and dreadful KRAS oncogenic mutations have bamboozled researchers for decades but their tireless efforts were fruitful. In 2021, two new targeted experimental therapies, AMG510 (sotorasib) and MRTX849 (adagrasib) were granted US Food and Drug Administration (FDA) approval. Sotorasib by Amgen is the first KRAS inhibitor specifically for G12C mutations in non-small cell lung cancer tumours. Adagrasib has similar pharmacological functionality. Both these drugs have been breakthrough innovations in the oncology world showing wondrous results in clinical trials including even complete disappearance of tumours.

“The three RAS oncogene products, KRAS, NRAS, and HRAS, which have frequency of ~30 per cent of human cancers, have been among the most interesting, sought after, and challenging targets. Pharmacologically targeting these intractable proteins is a key challenge of modern drug development, this space is buzzing with activity nonetheless. These require innovation and the development of new technologies. Thus, “difficult to drug” or “yet to be drugged” are perhaps more appropriate terms. I am not sure any such activity is here in India as most of such developments are by innovator companies. They require huge investment and long term work of extensive chemistry efforts”, said Praveen Sikri, CEO, Ikris Pharma Network.

Further, multiple biochemical or epigenetic anomalies are associated with undruggable cancers making them more perplexing. Aberrant PPIs are tricky to target using small molecules due to their large area of interaction and high hydrophobicity, like the protein interaction between c-Myc and MYC associated factor X or MAX.

According to Raheel Shah, Director, BDR Group of Companies, “Cancer is now a surfeit of potential molecular targets poised for therapeutic exploitation. Now, a number of validated and attractive cancer targets remain out of reach of pharmacological regulation. Some of these have been described as undruggable, at least by traditional techniques. Expanding the range of disease-relevant targets to pharmacological manipulation is central to reducing cancer mortality. Plenty of desirable targets in cancer are in this category, including the MYC and RAS oncogenes, and pharmacologically targeting these intractable proteins is now a major challenge in cancer research that needs development and innovation of new technologies.”

In July, 2021 a joint research effort between Indian Institute of Technology, Mandi and Department of Medicinal Chemistry, Banaras Hindu University, Varanasi discovered a novel molecule L755507 via computer-aided drug discovery, which can bind to c-Myc-MAX heterodimer with high affinity and low toxicity and is able to disrupt their interaction to reduce

expression. This has the potential to be developed into targeted therapy against cancers that show upregulation of Myc genetic products.

Jamia Millia Islamia Research Group headed by Dr Mohammad Husain, Department of Biotechnology, has recently published an exciting research finding on colorectal cancer. Colorectal cancer is the fifth most common cancer in India and has posed a serious concern due to its alarming occurrence, demanding early detection and treatment. They demonstrated that owing to possession of smaller mitochondria, colorectal cancer cells have a metabolic advantage of fermenting more glucose to lactate, a phenomenon called Warburg effect, which is characteristic of many undruggable cancers. Their research has unfolded future prospects in developing therapeutic routes for combating cancer.

“We hypothesised BRAFV600E driven metabolic reprogramming and cancer progression could be attributed to mitochondrial fission. Mitochondrial fission being a potent downstream effector of BRAFV600E, our results could serve as a therapeutic window of such treatment of refractory cancers. KRAS or BRAF oncogenic mutations are considered to be the driver of oncogenic mutations in various cancers including colorectal carcinomas and such oncogenic mutations pose various growth advantages to these cancers. Despite continued efforts, therapeutic targeting of cancers driven by KRAS/BRAF oncogenes has not been successful, thus necessitating the need to establish potential therapeutic modules downstream of these oncogenic events,” said Dr Husain.

“Due to the rapid pace of scientific advancement, yesterday’s ‘undruggable’ targets are now viable new research subjects, hence terms like ‘tough to drug’ or ‘still to be drugged’ may be more applicable.”

- Dr Niti Raizada,

Director - Medical Oncology and Hemato-Oncology and Transplant Physician, Fortis Hospital, Bengaluru

‘‘Plenty of desirable targets in cancer are in this category, including the MYC and RAS oncogenes, and pharmacologically targeting these intractable proteins is now a major challenge in cancer research that needs development and innovation of new technologies.”

- Raheel Shah, Director, BDR Group of Companies

“The CAR-T cells are popularly called ‘living drugs’ as T-cells are living cells, and they stay in the body forever. Treatment using imported technology may cost crores, but now a single dose treatment could be possible with about Rs 15 lakh.”

“Despite continued efforts, therapeutic targeting of cancers driven by KRAS/BRAF oncogenes has not been successful, thus necessitating the need to establish potential therapeutic modules downstream of these oncogenic events.” - Dr Mohammad Husain, Head, Department of Biotechnology, Jamia Millia Islamia

- Dr Rahul Purwar, Associate Professor, Department of Biosciences & Bioengineering, Indian Institute of Technology Bombay

“The three RAS oncogene products, KRAS, NRAS, and HRAS, which have frequency of ~30 per cent of human cancers have been among the most interesting, sought after, and challenging targets.”

- Praveen Sikri, Chief Executive Officer, Ikris Pharma Network

The marketability of druggability

Biologics are becoming the answer to questions that drugs cannot tackle. They have varied advantages when it comes to being used in cancer therapy. They help prime the body to attack cancer cells making affected cells more vulnerable to immune responses, enhance the immune system to

recognise cancer cells better and even help the body repair damaged cells faster. Thus, in all, they are quite useful in fending against cancer.

According to the Association of Biotechnology Led Enterprises (ABLE), India’s biologics market will grow at a compound annual growth rate (CAGR) of 22 per cent to hit $12 billion by 2025.

Biocon launched India’s first indigenously produced novel monoclonal antibody against solid tumours of epithelial origin mainly in head and neck cancer back in 2006 christened Nimotuzumab or BIOMAb-EGFR which targets the epidermal growth factor receptor (EGFR), present on cell surfaces. In cancerous cells, an overexpression of EGFR is observed leading to uncontrolled cell growth and angiogenesis- two typical characteristics of cancers and Nimotuzumab is able to arrest that. Currently, Biocon Biologics along with its Bostonbased associate, Bicara Therapeutics is developing a pipeline of biofunctional antibodies enabled by recent technological advances in immuno-oncology. They are in phase I of developing a tumour-targeted fusion mAB that will have the ability to target multiple tumour types and yield better therapeutic results.

Non-small cell lung cancer (NSCLC) exhibiting tumours with EGFR mutations can be targeted using tyrosine kinase inhibitors which are a vast range of therapeutics popularised since the breakthrough discovery of Imatinib Mesylate or Glivec in 2001 by Novartis. AstraZeneca Pharma India received import and market permission from the Drugs Controller General of India for Osimertinib 40mg/80mg film coated tablets (Tagrisso) in March, 2021. Osimertinib is now approved for adjuvant treatment after complete tumour resection in patients with NSCLC whose tumours have EGFR with particular deletion or substitution mutations in their coding areas.

In June, 2021, Alembic Pharmaceuticals announced that it has received final approval from the US FDA for its Abbreviated New Drug Application (ANDA) for Erlotinib Tablets, 25 mg, 100 mg, and 150 mg which will be therapeutically equivalent to the reference listed drug product (RLD), Tarceva tablets, 25 mg, 100 mg, and 150 mg, of OSI Pharmaceuticals, LLC. Erlotinib tablets are indicated for the treatment of patients with metastatic NSCLC with EGFR mutations.

Dr. Reddy’s Laboratories in Hyderabad has entered into a binding agreement with Singaporebased Prestige BioPharma for exclusive rights to commercialise and supply the latter’s trastuzumab biosimilar in select countries in Latin America and Southeast Asia. Prestige BioPharma’s trastuzumab (HD201) is a proposed biosimilar to Roche’s

Herceptin that is used for treatment of HER2 (human epidermal growth factor receptor) positive breast and metastatic gastric cancer.

With chimeric antigen receptor or CAR-T therapy being explored as a new avenue for treating undruggable cancer, a pilot clinical trial in India has been recently initiated as a joint collaboration between Indian Institute of Technology, Bombay (IIT-B) and Tata Memorial Hospital (TMH), Mumbai against certain difficult paediatric and adult blood cancers. The Central Government’s National Biopharma Mission- BIRAC (Biotechnology Industry Research Advisory Council) has approved Rs 19.15 crore to the team for conducting the first in-human phase 1/2 clinical trial using CAR-T cells.

“The CAR-T cells are popularly called ‘living drugs’ as T-cells are living cells, and they stay in the body forever. Developed in India, this technology will be affordable for larger sections of society. Treatment using imported technology may cost crores, but now a single dose treatment could be possible with about Rs 15 lakh”, said Dr Rahul Purwar, Associate Professor, Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay.

In spite of cancer being one of the most researched human problems across all fields of science in India, indigenous therapeutic molecules are rare, drug development is impaired and translational research is lacking. In terms of laboratory research and paper publication, India is one of the leading countries despite working with antiquated technology and dwindling funds. Yet, that research is rarely realized in clinical arenas.

With the burgeoning cancer burden, resources must be allocated to encourage drug discovery and R&D in pharmaceutical companies. Emphasis should be on innovation and invention instead of continuing the use of hackneyed techniques. Establishment of a streamlined communication system between the government, universities and research institutions and private sector companies is paramount to translate laboratory results into viable clinical products. This is the only way to quell the cancer rampage across our country.