An Investigation of How Telomerase Cancers can Switch to Become ALT Cancers
The paper I'll point out today is a timely one, given that the SENS Research Foundation's fundraiser for early stage work on a therapy for alternative lengthening of telomeres (ALT) cancers is nearing its close. There are still thousands of dollars left in the matching fund, so give it some thought if you haven't yet donated. The search for ways to safely sabotage ALT is a useful, important line of research because (1) blocking telomere lengthening is a path to a universal cancer therapy, (2) those research groups presently working on it are all looking to achieve this goal by interfering in the activities of telomerase, (3) cancers can switch from using telomerase to using ALT, and (4) next to no-one is working on ways to suppress ALT mechanisms. It seems fairly clear based on the evidence to date that the universal cancer therapy that lies ahead, built by inhibiting telomere lengthening, must involve a blockade of both telomerase and ALT. The open access paper below reinforces this point, the authors investigating how exactly cancers switch from telomerase to ALT to maintain their dangerous growth.
Cancer research today has a grand strategy problem. There is only so much funding and only so many researchers, but hundreds of subtypes of cancer. Therapies tend to be highly specific to the peculiarities of one type of cancer or a small class of cancers, meaning that great expense and time leads to a treatment that is only applicable for a fraction of cancer patients, all too often a tiny fraction. Further, since tumors evolve at great speed, any one individual patient's cancer may find its way out from under the hammer by changing its signature and mode of operation. All is not doom and gloom, however. Consider that the research community could build a therapy applicable to all cancers with little to no modification, where the cost of development would be no greater than any one of the highly specific therapies presently in use and under development. That therapy would be, of course, based on the blockade of telomere lengthening. The act of telomere lengthening is fundamental to all cancers, and without it tumors can neither grow nor sustain themselves: every cell loses a little of its telomeres with each division, and those with short telomeres self-destruct or become senescent. There is no expectation that any cancer would be able to evolve a way around a loss of telomere lengthening: these are core cellular mechanisms, not amenable to radical change or reinvention by simple mutational damage. The promise here is that the economics of cancer research and development could be entirely changed for the better, and that every cancer would become tractable, open to effective treatment.
The SENS Research Foundation cancer program staff propose to use an assay for ALT activity to assess the contents of the standard drug library for anti-ALT capabilities. The hope is that this will turn up potential candidates for further development, as well as shed more light on the most promising molecular mechanisms and targets to consider for the goal of shutting down ALT entirely, and further lend support for other groups to join in and help speed progress. In many ways ALT is a much easier target than telomerase. No normal adult cell uses ALT, so it is possible to take an indiscriminate, and therefore less costly approach to treatment without harming the patient. Telomerase is essential to stem cells, however, and so forms of targeting will be essential for that side of the future of cancer therapies. The paper linked here adds to the weight of evidence indicating that anti-ALT therapies are a necessary complement to the anti-telomerase therapies that are presently in the early stages of development.
Continuous telomere loss which derives from DNA replication, drives the fusion of chromosome ends, leads to cell cycle arrest and induces cell senescence. However, tumour cells can maintain telomere length and proliferation through telomerase reactivation or the alternative lengthening of telomeres (ALT) mechanism. It is reported that approximately 85-90% of cancer types are telomerase-positive, which use its RNA subunit (termed TR or TERC) as a template and its telomerase reverse transcriptase (TERT) to maintain chromosomal ends. Due to lack of telomerase activity in human somatic cells, telomerase is considered as a potential target of cancer therapy. However, this strategy would be ineffective in several human cancers, which are lack of detectable telomerase activity and utilize the ALT mechanism relying on recombination-mediated telomere elongation. Previous studies have shown that anti-telomerase therapy provoked a switch from telomerase activity to the ALT mechanism in mice. Furthermore, it has been shown that the ALT is an alternative mechanism for telomere maintenance during oncogenesis, which would ultimately decrease the effectiveness of anti-telomerase treatment. Therefore, identifying the mechanism of ALT induction and the telomerase-ALT switch is beneficial in resolving the bottlenecks of anti-telomerase therapy.
ALT-positive cells typically contain abnormally heterogeneous telomeres, ALT-associated promyelocytic leukaemia bodies (APBs) and extrachromosomal TTAGGG repeats (ECTRs). Despite understanding the hallmarks of ALT, the mechanism of ALT induction remains unknown. The study of ALT activation which transformed a telomerase-positive cell line into an ALT-positive cell line in vitro is rare. Recently, several factors have been shown to contribute to ALT formation. It has been reported that the depletion of a histone chaperon ASF1 resulted in ALT cells induction and long telomeres elongation concomitant with inhibition of telomerase activity. Since the ALT mechanism is a recombination-mediated lengthening mechanism, the clustering of telomeres caused by DNA damage response (DDR) promotes homology-directed telomere synthesis, suggesting that DDR may play an important role in ALT induction. Further, somatic mutations of the histone variant H3.3, alpha-thalassemia X-linked syndrome protein (ATRX) and death associated protein (DAXX) have been found in ALT cancers. They are chromatin remodeling factors at telomeres, which are responsible for ALT activity. Furthermore, it has been shown that ATRX inhibits ALT and relates to telomerase assembly and depositing. Although single and double deletion of ATRX and DAXX could not initiate the ALT mechanism, histone management dysfunction and chromatin structure disorder might provide a suitable genomic environment for ALT induction. Lastly, telomerase activity plays very important role in ALT repression. Inhibition of telomerase activity might promote ALT induction. It has been shown that genetic extinction of telomerase in T cells of ATM knockout mice results in tumor emergence, concomitant with the increase of APB and C-circles.
To determine the mechanism by which telomerase-positive cancer cells switch to ALT and to elucidate the mechanism of ALT induction, we induced telomere-specific DNA damage, disrupted the function of the ATRX/DAXX complex and inhibited telomerase activity in telomerase positive cancer cells, which successfully transformed a telomerase-positive cell line into a ALT-positive cell line.