This week, we had the honor of presenting three scientific posters at the 2016 Annual Meeting of the American Association of Cancer Research (AACR). Followers of DelMar have eagerly anticipated an update on our ongoing Phase I/II clinical trial in refractory glioblastoma, for which we were pleased to have presented continued promising results..
While we share in the excitement for our GBM trial update, we are equally as enthusiastic about the other two presentations, which were quite deep in their scientific detail. These types of presentations tend to go largely unnoticed by the investing public, but they serve as exciting “food for thought” for scientists in support of the scientific foundation for VAL-083 and its future. I wanted to take a moment to explain why …
Our strategy in drug development is to take compounds with prior clinical validation and study how they work against cancer. Our hope is that by employing cutting edge biological research systems to understand the way a drug attacks the tumor, we will learn how it is unique compared to currently available treatments. If the mechanism is unique, then the opportunity to go after cancers that are underserved by today’s therapies becomes our focus.
At AACR, our collaborators from MD Anderson and the University of British Columbia presented data showing that the mechanism of our lead compound, VAL-083, is distinct from other chemotherapies.
Specifically, we said: “Treatment with VAL-083 activated DNA damage signaling pathway as demonstrated by expression of phospho-ATM (S1981), phospho-Chk2 (T68), phospho-RPA32 (S33) and ?H2A.X and VAL-083 treatment led to long-lasting cell cycle arrest at S/G2 phase of the cell cycle, leading to DNA double-strand break that continue to accumulate for at least 72 hours demonstrating irreparable damage to the tumor cell.”
Why is this important?
First, all cells – cancer and normal – employ mechanisms to detect and repair damage. In the treatment of cancer, these mechanisms can give rise to drug resistance. If two drugs act differently, then it is more likely that a cancer resistant to one treatment might succumb to the other.
Second, the opportunity to combine two treatments is enhanced when they work differently. This is important because a tumor will employ multiple repair techniques to survive treatment. If two drugs work the same way, not only will there be cross-resistance, but their toxicities are likely to overlap too and it becomes difficult to combine the drugs safely. Different mechanisms usually mean that we can often attack the tumor from multiple angles – safely.
This is what is so exciting about the data we recently presented at AACR.DMPI- cell cycle
When a cell divides, it goes through four phases:
G1: The cell gets ready to copy its DNA
S: DNA is copied
G2: The cell gets ready to divide
M: The cell divides into two cells, each with one copy of the original cell’s DNA
Typically, a normal cell employs check-point control and DNA repair mechanisms to identify and repair damage during the G1 and G2 phases. A cell can halt itself during these parts of the cycle to fix damage, or if the damage cannot be fixed the cell decides to die through a process called apoptosis. The cell uses these tools to prevent damaged cells or DNA from propagating.
Cancer cells, by their very nature tend to have mutations or deficiencies in these mechanisms that may allow mistakes to persist. Mistakes that allow uncontrolled cell division become cancer.
Different chemotherapies cause the cell to stop within its cycle and, hopefully, due to this arrest cause the cancer cell to die. Unfortunately, this often causes cell death in normal cells as well.
Interestingly, VAL-083 doesn’t appear to cause significant toxicity in normal cells. The data we presented this week provides insight into this observation. The anti-cancer activity of our lead drug candidate, VAL-083, is due to the formation of DNA cross links. When the DNA tries to divide, the strands break. These “double strand breaks” are lethal to the tumor cell. A normal cell would identify these irregularities during its check points and halt the cell cycle and fix them through a process called homologous repair.
Many cancer cells have faulty check-points, so the cross-link goes unnoticed. Through our research, we have seen evidence of the cross links persisting for days on cancerous DNA. Once the cancer cell gets to the “S” phase and begins to unwind its DNA to be copied, the cross-link ends up causing a double strand break, which is lethal to the tumor cell.
Simply put, VAL-083 appears to take advantage of the very essence of what makes a cancer cell a cancer cell!
Following treatment with VAL-083, the tumor cells become “stuck” or “arrested” in the S-phase of replication and the damaged DNA does not move forward toward mitosis. This is particularly interesting in the context of combination therapy.
There is a class of compounds that have been used to treat a number of cancers called topoisomerase inhibitors (TOPO inhibitors). These drugs, including irinotecan used in the treatment of glioblastoma, have been hampered by side effects and a narrow therapeutic window.
TOPO inhibitors require a cell to be in the S-phase for their activity. Therefore, keeping enough of a TOPO inhibitor in the system to catch cells in the S-phase leads to toxicity and side effects.
Now that we know that VAL-083 causes cells to arrest in the S-phase, combining VAL-083 with TOPO inhibitors becomes an extremely interesting proposition – to reduce side effects and enhance tumor killing!
So, what we’ve learned so far about the VAL-083 mechanism helps to explain the drug’s favorable safety profile, why it is able to treat cancers resistant to other chemotherapies and also defines opportunities for potential combination therapies in the treatment of cancer.
Oh, and another exciting thing about a unique mechanism … being different is valuable. Taxol leaped from a modest $200 million in sales to several billion once scientists understood its unique mechanism.
http://www.thechairmansblog.com/delmar-pharmaceuticals/jeffrey-bacha/mechanism-matters/
Recent KTRA News
- Kintara Therapeutics Announces Expansion of REM-001 Clinical Study to Include Patients on Pembrolizumab • PR Newswire (US) • 03/27/2024 01:00:00 PM
- Form 8-K - Current report • Edgar (US Regulatory) • 02/27/2024 11:59:49 AM
- Form 8-K - Current report • Edgar (US Regulatory) • 02/26/2024 12:00:25 PM
- Form 8-K - Current report • Edgar (US Regulatory) • 02/22/2024 12:00:10 PM
- Kintara Therapeutics Announces Fiscal 2024 Second Quarter Financial Results and Provides Corporate Update • PR Newswire (US) • 02/14/2024 09:07:00 PM
- Form 8-K - Current report • Edgar (US Regulatory) • 02/12/2024 02:05:27 PM
- Kintara Therapeutics Announces Initiation of REM-001 Clinical Trial for the Treatment of Cutaneous Metastatic Breast Cancer • PR Newswire (US) • 02/12/2024 02:00:00 PM
- Form 8-K - Current report • Edgar (US Regulatory) • 12/18/2023 09:10:10 PM
- Form 424B5 - Prospectus [Rule 424(b)(5)] • Edgar (US Regulatory) • 12/18/2023 09:05:21 PM
- Form 8-K - Current report • Edgar (US Regulatory) • 12/15/2023 09:15:08 PM
- Form 8-K - Current report • Edgar (US Regulatory) • 12/07/2023 02:10:19 PM
- Kintara Therapeutics Announces Review of Strategic Alternatives • PR Newswire (US) • 12/07/2023 02:00:00 PM
- Form 8-K - Current report • Edgar (US Regulatory) • 12/05/2023 02:10:08 PM
- Kintara Therapeutics Granted Extension by Nasdaq to Regain Compliance with the Stockholders' Equity Continued Listing Requirement • PR Newswire (US) • 12/05/2023 02:00:00 PM
- Form 8-K - Current report • Edgar (US Regulatory) • 11/21/2023 12:55:37 PM
- Form 8-K - Current report • Edgar (US Regulatory) • 11/13/2023 09:15:23 PM
- Kintara Therapeutics Announces Fiscal 2024 First Quarter Financial Results and Provides Corporate Update • PR Newswire (US) • 11/13/2023 09:10:00 PM
- Form 10-Q - Quarterly report [Sections 13 or 15(d)] • Edgar (US Regulatory) • 11/13/2023 09:05:42 PM
- Form 8-K - Current report • Edgar (US Regulatory) • 10/31/2023 12:10:08 PM
- Kintara Therapeutics Announces Preliminary Topline Results From GBM AGILE Study • PR Newswire (US) • 10/31/2023 12:00:00 PM
- Form S-1/A - General form for registration of securities under the Securities Act of 1933: [Amend] • Edgar (US Regulatory) • 10/27/2023 08:05:48 PM
- Form S-1/A - General form for registration of securities under the Securities Act of 1933: [Amend] • Edgar (US Regulatory) • 10/24/2023 08:43:48 PM
- Form 8-K - Current report • Edgar (US Regulatory) • 10/10/2023 08:06:50 PM
- Form S-1 - General form for registration of securities under the Securities Act of 1933 • Edgar (US Regulatory) • 10/04/2023 08:35:08 PM
- Form 8-K - Current report • Edgar (US Regulatory) • 09/26/2023 08:09:24 PM
FEATURED POET and MultiLane Collaborate to Develop High-Speed Pluggable Transceivers for AI Networks • Mar 27, 2024 10:52 AM
Endexx Corporation (EDXC) Leverages Global Market Trends and Legislative Reforms to Spearhead Growth in the Cannabis and Plant-Based Wellness Sectors • EDXC • Mar 27, 2024 3:01 PM
Applied UV, Inc. Announces Pricing of $2.76 Million Registered Direct and Private Placement Priced at the Market Under Nasdaq Rules • AUVI • Mar 27, 2024 2:51 PM
Maybacks Global Entertainment Opens 23 More Stations in Important Major Cities • AHRO • Mar 27, 2024 9:00 AM
NxGen Brands Inc. Forecast to Deliver 140% Growth in Q1 2024 • NXGB • Mar 27, 2024 7:30 AM
Kona Gold Beverages, Inc. Strategic Advancements: Covert LLC Introduces Federally Legal D9 Gummies and Revamps Innovative eCommerce Platform, Propelling Toward $12 Million Annual Revenue Goal • KGKG • Mar 26, 2024 8:30 AM